New bicyclic derivatives

ABSTRACT

which are useful in the control of endoparasites, for example heartworms, in warm-blooded animals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application62/858,465, filed Jun. 7, 2019, and to U.S. Provisional Application62/947,852, filed Dec. 13, 2019, the content of each which is hereinincorporated by reference in its entirety.

FIELD

The present invention relates to medicinal chemistry, pharmacology, andveterinary and human medicine. More particularly, the present inventionrelates to compounds of formula (I) and their use in the control ofendoparasites, for example heartworms, in warm-blooded animals.

BACKGROUND

Heartworm (Dirofilaria immitis) is a parasitic roundworm that is spreadfrom host to host through the bites of mosquitoes. The lifecycle startswhen a female mosquito takes a blood meal from an infected host. Themosquito ingests immature heartworms which then molt to the infectivelarvae stage and travel to the mosquitoes' mouth parts. The mosquitothen feeds on a susceptible host, such as a dog or cat, depositing theinfective larvae. The larvae then molt to the next larval stage in thenew host and then migrate through the body, eventually ending up in theblood vessels. As the larvae migrate through the tissues they molt intojuvenile adults. The juvenile adults eventually move into the bloodvessels of the lungs where they mature into sexually active adults. Theadult heartworms then breed and release immature heartworms completingthe cycle. Heartworm infection may result in serious disease for thehost.

Adult heartworm infections may be treated with arsenic-based compounds;the treatment is time consuming, cumbersome, and often only partlysuccessful. Accordingly, treatment is focused on the control ofheartworm infection. Heartworm control is currently performedexclusively by year round periodical administration of drugs. Typicaltreatments include macrocyclic lactones such as ivermectin, moxidectin,and milbemycin oxime. Unfortunately, developing resistance ofDirofilaria immitis to macrocyclic lactones has been observed.Accordingly, there is a need for new compounds which effectively controlheartworm infections either by way of prophylaxis or by directly killingheartworms. Certain treatments of endoparasites are described in WO2017/178416, WO 2018/087036, WO 2018/197401, WO 2019/025341, and WO2019/002132.

SUMMARY

The present invention provides compounds of formula (I) whicheffectively treat and/or control endoparasites (e.g., heartworm) inwarm-blooded animals.

In one embodiment, the present invention provides compounds of formula(I):

wherein

-   -   n is 0 or 1;    -   X₁ is selected from the group consisting of N and CR₁;    -   X₂ is selected from the group consisting of N and CR₂;    -   X₃ is selected from the group consisting of N and CR₃;    -   X₄ is selected from the group consisting of N and CR₄;    -   X₅ is selected from the group consisting of N and CR₅;    -   X₆ is selected from the group consisting of N and CR₆;    -   G is selected from the group consisting of

-   -   M is selected from the group consisting of N—R₁₃, O, and S;    -   Y₁ is selected from the group consisting of CR₈R₉, O, S, and        NR₁₀;    -   Y₂ is selected from the group consisting of CR₈R₉, O, S, and        NR₁₀;        -   wherein at least one of the groups Y₁ or Y₂ is CR₈R₉,    -   Z₁ is selected from the group consisting of N, O, S, and CR₁₁;    -   Z₂ is selected from the group consisting of nil, N, and CR₁₁;    -   Z₃ is selected from the group consisting of nil, N and CR₁₁;    -   Z₄ is selected from the group consisting of N, O, S, and CR₁₁;        -   wherein no more than 2 of Z₁, Z₂, Z₃, and Z₄ are N and            wherein only one of Z₁ and Z₄ is O or S, Z₂ is nil only when            Z₁ is O or S, and Z₃ is nil only when Z₄ is O or S;    -   R₁ is selected from the group consisting of hydrogen, halogen,        hydroxyl, —SH, —SC₁-C₄ alkyl, —S(O)(C₁-C₄ alkyl), —S(O)₂(C₁-C₄        alkyl), cyano, C₁-C₄ alkyl, C₁-C₄ halogenoalkyl, C₁-C₄-alkoxy,        —B(OR₁₅)(OR₁₆) wherein R₁₅ is, each time taken, selected from        the group consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆        cycloalkyl, R₁₆ is, each time taken, selected from the group        consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or        R₁₅ and R₁₆ together with the oxygen atoms to which they are        attached form a 5- to 7-membered ring which is optionally        substituted with 1 to 4 C₁-C₄ alkyl; —NH₂, —NH(C₁-C₄ alkyl), and        —N(C₁-C₄ alkyl)₂;    -   R₂ is selected from the group consisting of hydrogen, halogen,        hydroxyl, —SH, —SC₁-C₄ alkyl, —S(O)(C₁-C₄ alkyl), —S(O)₂(C₁-C₄        alkyl), cyano, C₁-C₄ alkyl, C₁-C₄ halogenoalkyl, C₁-C₄-alkoxy,        —B(OR₁₅)(OR₁₆) wherein R₁₅ is, each time taken, selected from        the group consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆        cycloalkyl, R₁₆ is, each time taken, selected from the group        consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or        R₁₅ and R₁₆ together with the oxygen atoms to which they are        attached form a 5- to 7-membered ring which is optionally        substituted with 1 to 4 C₁-C₄ alkyl; —NH₂, —NH(C₁-C₄ alkyl), and        —N(C₁-C₄ alkyl)₂;    -   R₃ is selected from the group consisting of hydrogen, halogen,        hydroxyl, —SH, —SC₁-C₄ alkyl, —S(O)(C₁-C₄ alkyl), —S(O)₂(C₁-C₄        alkyl), cyano, C₁-C₄ alkyl, C₁-C₄ halogenoalkyl, C₁-C₄-alkoxy,        —B(OR₁₅)(OR₁₆) wherein R₁₅ is, each time taken, selected from        the group consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆        cycloalkyl, R₁₆ is, each time taken, selected from the group        consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or        R₁₅ and R₁₆ together with the oxygen atoms to which they are        attached form a 5- to 7-membered ring which is optionally        substituted with 1 to 4 C₁-C₄ alkyl; —NH₂, —NH(C₁-C₄ alkyl), and        —N(C₁-C₄ alkyl)₂;    -   R₄ is selected from the group consisting of halogen, cyano,        —CHO, hydroxyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆        cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄-alkoxy substituted-C₁-C₄        alkyl, benzyl optionally substituted with 1 to 5 halogen atoms,        C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,        —NH(C₃-C₆ cycloalkyl), —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl),        —N(C₁-C₄ alkyl)(4- to 7-membered heterocycloalkyl), —NH(4- to        7-membered heterocycloalkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkoxy),        —C(O)NH(C₁-C₄ alkyl), —C(O)N(C₁-C₄ alkyl)₂, —C(O)N(C₁-C₄        alkyl)(4- to 7-membered heterocycloalkyl), —NHSO₂(C₁-C₄ alkyl),        —SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl, —B(OR₁₅)(OR₁₆)        wherein R₁₅ is, each time taken, selected from the group        consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, R₁₆        is, each time taken, selected from the group consisting of        hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or R₁₅ and R₁₆        together with the oxygen atoms to which they are attached form a        5- to 7-membered ring which is optionally substituted with 1 to        4 C₁-C₄ alkyl; 6- or 10 membered aryl; a monocyclic heterocycle        selected from the group of 4- to 7-membered heterocycloalkyl,        5-membered heteroaryl having at least one nitrogen atom via        which the 5-membered heteroaryl ring is connected to the rest of        the molecule, and 6-membered heteroaryl having at least one        nitrogen atom; each of the aryl, heterocycloalkyl, and        heteroaryl rings in R₄ is optionally substituted with 1, 2 or 3        substituents independently selected from the group consisting of        halogen, cyano, nitro, hydroxy, oxo, C₁-C₄ alkyl, C₃-C₆        cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄        alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl), —N(C₁-C₄        alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl), —SC₁-C₄ alkyl,        —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl, —S(O)C₁-C₄-halogenoalkyl and        —SO₂C₁-C₄ halogenoalkyl; wherein the C₃-C₆ cycloalkyl and the        heterocycloalkyl rings in R₄ are optionally substituted with a        spiro group, wherein said spiro group is a 3- to 6-membered        cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1, 2,        or 3 heteroatoms independently selected from N, S or O, wherein        said spiro group is optionally substituted with 1, 2 or 3        substituents independently selected from the group consisting of        halogen, cyano, nitro, hydroxy, oxo, C₁-C₄ alkyl, C₃-C₆        cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄        alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl), —N(C₁-C₄        alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl), —SC₁-C₄ alkyl,        —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl, —S(O)C₁-C₄-halogenoalkyl and        —SO₂C₁-C₄ halogenoalkyl; and wherein each C₁-C₄ alkyl, C₃-C₆        cycloalkyl and C₁-C₄ alkoxy in R₄ may be optionally substituted        with 1, 2 or 3 substituents independently selected from the        group consisting of halogen, hydroxy, —NH₂, —NH(C₁-C₄ alkyl),        —N(C₁-C₄ alkyl)₂, cyano, carboxy, carbamoyl, C₁-C₄        alkoxycarbonyl, —C(O)NH(C₁-C₄ alkyl), —C(O)N(C₁-C₄ alkyl)₂, and        C₁-C₄ alkoxy;    -   R₅ is selected from the group consisting of hydrogen, halogen,        hydroxyl, —SH, —SC₁-C₄ alkyl, —S(O)(C₁-C₄ alkyl), —S(O)₂(C₁-C₄        alkyl), cyano, C₁-C₄ alkyl, C₁-C₄ halogenoalkyl, C₁-C₄-alkoxy,        —B(OR₁₅)(OR₁₆) wherein R₁₅ is, each time taken, selected from        the group consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆        cycloalkyl, R₁₆ is, each time taken, selected from the group        consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or        R₁₅ and R₁₆ together with the oxygen atoms to which they are        attached form a 5- to 7-membered ring which is optionally        substituted with 1 to 4 C₁-C₄ alkyl; —NH₂, —NH(C₁-C₄ alkyl), and        —N(C₁-C₄ alkyl)₂;    -   R₆ is selected from the group consisting of hydrogen, halogen,        hydroxyl, —SH, —SC₁-C₄ alkyl, —S(O)(C₁-C₄ alkyl), —S(O)₂(C₁-C₄        alkyl), cyano, C₁-C₄ alkyl, C₁-C₄ halogenoalkyl, C₁-C₄-alkoxy,        —B(OR₁₅)(OR₁₆) wherein R₁₅ is, each time taken, selected from        the group consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆        cycloalkyl, R₁₆ is, each time taken, selected from the group        consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or        R₁₅ and R₁₆ together with the oxygen atoms to which they are        attached form a 5- to 7-membered ring which is optionally        substituted with 1 to 4 C₁-C₄ alkyl; —NH₂, —NH(C₁-C₄ alkyl), and        —N(C₁-C₄ alkyl)₂;    -   R₇ is selected from the group consisting of hydrogen, C₁-C₄        alkyl, and C₃-C₆ cycloalkyl optionally substituted with 1 to 5        halogen atoms, —C(H)O, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄        halogenoalkyl, and C₁-C₄-alkoxy;    -   R₈ is, each time selected, independently selected from the group        consisting of hydrogen, fluoro, and C₁-C₄ alkyl;    -   R₉ is, each time selected, independently selected from the group        consisting of hydrogen, fluoro, and C₁-C₄ alkyl;    -   R₁₀ is selected from the group consisting of hydrogen and C₁-C₄        alkyl;    -   R₁₁ is, each time selected, independently selected from the        group consisting of hydrogen, halogen, hydroxyl, cyano, C₁-C₄        alkyl, C₁-C₄ halogenoalkyl, C₁-C₄-alkoxy, C₃-C₆ cycloalkyl,        —NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂; and    -   Q is selected from the group consisting of    -   (i) 6- or 10 membered aryl optionally substituted with 1, 2, 3,        4, or 5 substituents independently selected from the group        consisting of halogen, cyano, nitro, hydroxyl, C₁-C₄ alkyl,        C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, —NH₂,        —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl),        —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl), —SC₁-C₄        alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,        —S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl, wherein        the 6- or 10 membered aryl is optionally fused with a 4- to        7-membered heterocycloalkyl having 1 or 2 heteroatoms selected        from the group O, S, and N and wherein the carbons of the        heterocycloalkyl are optionally substituted with 1, 2 or 3        substituents independently selected from the group halogen,        cyano, nitro, hydroxyl, oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,        C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl), and        —N(C₁-C₄ alkyl)₂ and any N in the heterocycloalkyl is, valency        permitting, substituted with a substituent selected from the        group consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl;    -   (ii) 5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms        independently selected from the group O, S, and N and wherein        the carbons of the 5- to 10-membered heteroaryl are optionally        substituted with 1, 2, 3, 4, or 5 substituents independently        selected from the group consisting of halogen, cyano, nitro,        hydroxyl, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl,        C₁-C₄ alkoxy, benzyloxy, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄        alkyl)₂, —SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,        —S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl, and any N        in the heteroaryl, valency permitting, is optionally substituted        with a substituent selected from the group consisting of        hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl;    -   (iii) 4- to 7-membered heterocycloalkyl having 1, 2, or 3        heteroatoms independently selected from the group O, S, N,        wherein the heterocycloalkyl is optionally benzo-fused, wherein        the carbons of the 4- to 7-membered heterocycloalkyl or        optionally benzo-fused 4- to 7-membered heterocycloalkyl are        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from the group consisting of halogen,        cyano, nitro, hydroxyl, oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,        C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl), and        —N(C₁-C₄ alkyl)₂ and any N in the heterocycloalkyl is optionally        substituted with a substituent selected from the group        consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl;    -   (iv) 6- or 10 membered aryloxy optionally substituted with 1, 2        or 3 substituents independently selected from the group        consisting of halogen, cyano, nitro, hydroxyl, C₁-C₄ alkyl,        C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂,        —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl),        —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl), —SC₁-C₄        alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,        —S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl;    -   (v) 6- or 10 membered arylthio-oxy optionally substituted with        1, 2 or 3 substituents independently selected from the group        consisting of halogen, cyano, nitro, hydroxyl, C₁-C₄ alkyl,        C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂,        —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl),        —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl), —SC₁-C₄        alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,        —S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl; and    -   (vi) 5- to 10-membered heteroaryloxy optionally substituted with        1, 2 or 3 substituents independently selected from the group        consisting of halogen, cyano, nitro, hydroxyl, oxo, C₁-C₄ alkyl,        C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂,        —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl),        —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl), —SC₁-C₄        alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,        —S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl;    -   R₁₃ is selected from the group consisting of hydroxy, C₁-C₄        alkoxy, and —NH₂; and    -   R₁₄ is, each time selected, independently selected from the        group consisting of hydrogen, halogen, cyano, nitro, hydroxyl,        C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄        alkoxy, C₁-C₄ halogenalkoxy, —NH₂, —NH(C₁-C₄ alkyl), and        —N(C₁-C₄ alkyl)₂;    -   or a salt thereof.

In one embodiment, the present invention also provides compositions,comprising: a compound of formula (I) or a salt thereof and anacceptable excipient, the composition optionally further comprising atleast one additional active compound.

In one embodiment, the present invention also provides a method fortreating parasites, comprising: administering to a subject in needthereof an effective amount of a compound of formula (I) or a saltthereof, the method optionally further comprising an effective amount ofat least one additional active compound.

In one embodiment, the present invention also provides a method forcontrolling parasites, comprising: administering to a subject in needthereof an effective amount of a compound of formula (I) or a saltthereof, the method optionally further comprising an effective amount ofat least one additional active compound.

In one embodiment, the present invention also provides a method fortreating or controlling parasites, comprising: contacting a subject'senvironment with an effective amount of a compound of formula (I) or asalt thereof, the method optionally further comprising an effectiveamount of at least one additional active compound.

Thus, the invention provides for the use of the compounds of theinvention as a medicament, including for the manufacture of amedicament. In one embodiment, the invention provides the manufacture ofa medicament comprising a compound of formula (I) or a salt thereof fortreating parasites. In one embodiment, the invention provides themanufacture of a medicament comprising a compound of formula (I) or asalt thereof for controlling parasites.

The present invention also provides processes from making compounds ofthe invention and intermediates thereof.

DETAILED DESCRIPTION

The term “C₁-C₄ alkyl” refers to a straight or branched alkyl chainhaving from one to four carbon atoms and includes methyl, ethyl, propyl,isopropyl, butyl, and the like.

The term “C₁-C₄ halogenoalkyl” refers to a straight or branched alkylchain having from one to four carbon atoms and 1 to 5 halogen andincludes fluoromethyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, 1,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, andthe like.

The term “C₂-C₄ alkenyl” refers to a straight or branched alkenyl chainhaving from two to four carbon atoms and one carbon-carbon double bond,and includes ethylene, propylene, iso-propylene, butylene, iso-butylene,sec-butylene, and the like.

The term “C₂-C₄ alkynyl” refers to a straight or branched alkynyl chainhaving from two to four carbon atoms and one carbon-carbon triple bond,and includes acetylene, propargyl, and the like.

The term “C₁-C₄ alkoxy” refers to a C₁-C₄ alkyl attached through anoxygen atom and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy,and the like.

The term “C₃-C₆ cycloalkyl” refers to an alkyl ring of three to sixcarbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The terms “halogen” and “halogeno” refers to a chloro, fluoro, bromo oriodo atom.

The term “C₆- or C₁₀-membered aryl” refers to phenyl or naphthyl.

The term “C₆- or C₁₀-membered aryloxy” refers to phenyl or naphthylattached through an oxygen atom and includes phenoxy and naphtyloxy.

The term “C₆- or C₁₀-membered arylthio-oxy” refers to phenyl or naphthylattached through an sulfur atom and includes phenthio-oxy andnaphtylthio-oxy. Further it is understood that the term “C₆- orC₁₀-membered arylthio-oxy” also encompasses in which the sulfur is the—SO₂— and —S(O)—.

The term “4- to 7-membered heterocycloalkyl” refers to a 4 to 7 memberedmonocyclic saturated or partially (but not fully) unsaturated ringhaving one or more heteroatoms, preferably one, two, or threeheteroatoms, selected from the group consisting of nitrogen, oxygen, andsulfur and the ring optionally includes a carbonyl to form a lactam orlactone. It is understood that where sulfur is included that the sulfurmay be either —S—, —SO—, or —SO₂—. For example, but not limiting, theterm includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, oxetanyl, dioxolanyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrofuryl, hexahydropyrimidinyl,tetrahydropyrimidinyl, dihydroimidazolyl, and the like.

The term “5-membered heteroaryl” refers to a five membered, monocyclic,fully unsaturated, ring with one to four carbon atoms and one to fourheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur. For example, but not limiting, the term includes furyl, thienyl,pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl,thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and the like. It isunderstood that a 5-membered heteroaryl can be attached as a substituentthrough a ring carbon or a ring nitrogen atom where such an attachmentmode is available, for example for a pyrrolyl, imidazolyl, pyrazolyl,triazolyl, and the like.

The term “6-membered heteroaryl” refers to a six membered, monocyclic,fully unsaturated ring with one to five carbon atoms and one or more,typically one to four, heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur. For example, but not limiting, the termincludes pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, and thelike. It is understood that a 6-membered heteroaryl can be attached as asubstituent through a ring carbon or a ring nitrogen atom where such anattachment mode is available.

The term “5- to 10-membered heteroaryl” refers to a five to tenmembered, monocyclic or polycyclic fully unsaturated, ring or ringsystem with one to nine carbon atoms and one or more heteroatoms,preferably one, two, or three heteroatoms, selected from the groupconsisting of nitrogen, oxygen, and sulfur. For example, but notlimiting, the term includes furyl, thienyl, pyrrolyl, imidazolyl,isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, azepinyl, diazepinyl,benzofuryl, benzothienyl, indolyl, isoindolyl, benzimidazolyl,benzisothiazolyl, benzisoxazolyl, benzoxazolyl, benzopyrazinyl,benzopyrazolyl, quinazolyl, thienopyridyl, quinolyl, isoquinolylbenzothiazolyl, and the like. It is understood that a 5- to 10-memberedheteroaryl having 1, 2, or 3 heteroatoms selected from the group O, S,and N can be attached as a substituent through a ring carbon or a ringnitrogen atom where such an attachment mode is available.

The term “5- to 10-membered heteroaryloxy” refers to a 5- to 10-memberedheteroaryl having one or more heteroatoms, preferably 1, 2, or 3heteroatoms, selected from the group O, S, and N, attached through anoxygen atom and includes imidazolyloxy, pyrazolyloxy, pyridyloxy,pyrimidyloxy, quinolyloxy, and the like.

The term “oxo” refers to an oxygen atom doubly bonded to the carbon towhich it is attached to form the carbonyl of a ketone or aldehyde. Forexample, a pryidone radical is contemplated as an oxo substituted6-membered heteroaryl.

The term “carboxyl” refers to the group below:

The term “carbamoyl” refers the group below:

The term “C₁-C₄ alkoxy carbonyl” refers the group below:

wherein R is a C₁-C₄ alkyl.

The term “nil” as used herein with reference to a group, substituent,moiety, or the like, indicates that that group, substituent, or moietyis not present. Wherein a group, substituent, or moiety is ordinarilybonded to two or more other groups, substituents, or moieties, theothers are bonded together in lieu of the group, substituent, or moietywhich is nil. For example, with a compound having the structure A-B-C;wherein B is nil, then A is directly bonded to C and the compound isA-C. As another example, with a compound having the structure A-B-C;wherein C is nil, then the compound is A-B.

The term “salt” refers to salts of veterinary or pharmaceuticallyacceptable organic acids and bases or inorganic acids and bases. Suchsalts are well known in the art and include those described in Journalof Pharmaceutical Science, 66, 2-19 (1977). An example is thehydrochloride salt.

The term “substituted,” including when used in “optionally substituted”refers to one or more hydrogen radicals of a group being replaced withnon-hydrogen radicals (substituent(s)). It is understood that thesubstituents may be either the same or different at every substitutedposition. Combinations of groups and substituents envisioned by thisinvention are those that are stable or chemically feasible. Forcompounds described herein, groups and substituents thereof may beselected in accordance with permitted valence of the atoms and thesubstituents, such that the selections and substitutions result in astable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.

It is understood that when a cycloalkyl or heterocycloalkyl ring issubstituted with a spiro group, the spiro group can be attached, valencypermitting, to any position of the cycloalkyl or heterocycloalkyl,forming an additional ring such that the spiro group is attached to thecycloalkyl or heterocycloalkyl ring through a common atom. Examples ofsuch spiro substituted rings include 2-oxa-6-azaspiro[3.3]heptane,2-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane,6-oxa-2-azaspiro[3.4]octane, and the like.

The term “stable” refers to compounds that are not substantially alteredwhen subjected to conditions to allow for their production. In anon-limiting example, a stable compound or chemically feasible compoundis one that is not substantially altered when kept at a temperature of40° C. or less, in the absence of moisture or other chemically reactiveconditions, for about a week.

It is understood that, where the terms defined herein mention a numberof carbon atoms, that the mentioned number refers to the mentioned groupand does not include any carbons that may be present in any optionalsubstituent(s) thereon or any carbons that may be present as part of afused ring, including a benzo-fused ring.

The skilled artisan will appreciate that certain of the compounds of thepresent invention exist as isomers. All stereoisomers of the compoundsof the invention, including geometric isomers, enantiomers, anddiastereomers, in any ratio, are contemplated to be within the scope ofthe present invention.

The skilled artisan will also appreciate that certain of the compoundsof the present invention exist as tautomers. All tautomeric forms thecompounds of the invention are contemplated to be within the scope ofthe present invention.

Compounds of the invention also include all isotopic variations, inwhich at least one atom of the predominant atom mass is replaced by anatom having the same atomic number, but an atomic mass different fromthe predominant atomic mass. Use of isotopic variations (e.g.,deuterium, 41) may afford greater metabolic stability. Additionally,certain isotopic variations of the compounds of the invention mayincorporate a radioactive isotope (e.g., tritium, ³H, or ¹⁴C), which maybe useful in drug and/or substrate tissue distribution studies.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, may be useful in Positron Emission Topography (PET) studies.

The terms “compounds of the invention” and “a compound of the invention”and “compounds of the present invention” and a like include theembodiment of formula (I) and the other more particular embodimentsencompassed by formula (I) described herein and the exemplifiedcompounds described herein and a salt of each of these embodiments.

The compound of formula (I) with G as defined has the formulae:

Further embodiments of compounds of the invention are provided below:

(a) One embodiment relates to a compound of formula (Ia).(b) One embodiment relates to a compound of formula (Ib).(1) One embodiment relates to a compound of formula (Ic).(2) One embodiment relates to a compound of formula (I), embodiments(a), embodiment (b), and (1) wherein at least one of X₁, X₂, X₃, and X₅is N.(c) One embodiment relates to compounds of formula (I), formula (Ia),formula (Ib), or formula (Ic) wherein X₁ is CR₁; X₂ is CR₂; X₃ is CR₃;X₄ is CR₄; X₅ is CR₅; and X₆ is N; or a salt thereof.(d) One embodiment relates to compounds of formula (I), formula (Ia),formula (Ib), or formula (Ic) wherein X₁ is CR₁; X₂ is CR₂; X₃ is CR₃;X₄ is CR₄; X₅ is N; and X₆ is N; or a salt thereof.(e) One embodiment relates to compounds of formula (I), formula (Ia), orformula (Ib)) wherein X₁ is CR₁; X₂ is CR₂; X₃ is CR₃; X₄ is CR₄; X₅ isN; and X₆ is CR₆; or a salt thereof.(f) One embodiment relates to compounds of formula (I), formula (Ia),formula (Ib), or formula (Ic) wherein X₁ is CR₁; X₂ is CR₂; X₃ is CR₃;X₄ is N; X₅ is N; and X₆ is N; or a salt thereof.(g) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 6- or 10membered aryl optionally substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, cyano,nitro, hydroxyl, C₁-C₄ alkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, C₃-C₆cycloalkyl, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆cycloalkyl), —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl),—SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,—S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl; or a salt thereof.(h) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is 6-membered aryloptionally substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of halogen, cyano, nitro, hydroxyl,C₁-C₄ alkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, —NH₂,—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl), —N(C₁-C₄alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl), —SC₁-C₄ alkyl, —S(O)C₁-C₄alkyl, —SO₂C₁-C₄ alkyl, —S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄halogenoalkyl, wherein the 6-membered aryl is fused with a 4- to7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from thegroup O, S, and N and wherein the carbons of the heterocycloalkyl areoptionally substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of halogen, cyano, nitro, hydroxyl,oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy,—NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂ and any N in theheterocycloalkyl is substituted with a substituent selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl; or asalt thereof.(i) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 5- to10-membered heteroaryl having 1 or 2 heteroatoms selected from the groupO, S, and N and wherein the carbons of the heteroaryl are optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halogen, cyano, nitro, —OH, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl),and —N(C₁-C₄ alkyl)₂ and any N in the heteroaryl is optionallysubstituted with a substituent selected from the group consisting ofhydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl; or a salt thereof.(j) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 4- to7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from thegroup O, S, N, wherein the heterocycloalkyl is optionally benzo-fused,wherein the carbons of the heterocycloalkyl or optionally benzo-fusedheterocycloalkyl are optionally substituted with 1, 2, 3, or 4substituents independently selected from the group consisting ofhalogen, cyano, nitro, hydroxyl, oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄alkyl)₂ and any N in the heterocycloalkyl is optionally substituted witha substituent selected from the group consisting of hydrogen, C₁-C₄alkyl, and C₃-C₆ cycloalkyl; or a salt thereof.(k) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 6- or 10membered aryloxy optionally substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, cyano,nitro, hydroxyl, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl,C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆cycloalkyl), —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl),—SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,—S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl; or a salt thereof.(l) One embodiment relates to a compound of formula (I) and embodiments(1), (2), (a), (b), (c), (d), (e) and (f) wherein Q is a and 5- to10-membered heteroaryloxy optionally substituted with 1, 2 or 3substituents independently selected from the group consisting ofhalogen, cyano, nitro, hydroxyl, oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —NH(C₃-C₆ cycloalkyl), C₄ alkyl)(C₃-C₆-cycloalkyl),—NHSO₂(C₁-C₄ alkyl), —SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,—S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl; or a salt thereof.(m) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e) (f), (g), (h), (i), (j), (k), and (1)wherein n is 1; or a salt thereof.(n) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e) and (f), (g), (h), (i), (j), (k), (1),and (m) wherein Y₁ is CR₈R₉ and Y₂ is O; or a salt thereof;(o) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e) (f), (g), (h), (i), (j), (k), (1),(m), and (n) wherein R₄ is selected from the group consisting of C₁-C₄alkyl, C₃-C₆ cycloalkyl, —N(C₁-C₄ alkyl)₂, and 4- to 7-memberedheterocycloalkyl; or a salt thereof.(p) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e), (f), (1), (2), (g), (h), (i), (j),(k), (1), (m), and (n) wherein R₄ is —N(C₁-C₄ alkyl)₂; or a saltthereof.(q) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1),(m), (n), (o), and (p) wherein M is O; or a salt thereof.(r) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1),(m), (n), (o), and (p) wherein M is NR₁₃; or a salt thereof.(s) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1),(m), (n), (o), and (p) wherein M is S; or a salt thereof.(t) One embodiment relates to a compound of formula (I) and embodiments(a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1),(m), (n), (o), (p), (q), (r), and (s) wherein Z₁ is CR₁₁, Z₂ is CR₁₁, Z₃is nil, and Z₄ is S; or a salt thereof.(u) Another embodiment relates to a salt of each of the exemplifiedcompounds.

Another embodiment provides compounds of formulae:

-   -   or a salt of any of the foregoing;    -   wherein X₁, X₂, X₃, X₄, X₅, X₆, R₁, R₄, R₅, R₇, and Q are as        defined in the Summary.

In another embodiment for formula (Ia-1) through (Ia-8a) [i.e., formulae(Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-1a),(Ia-2a), (Ia-3a), (Ia-4a), (Ia-5a), (Ia-6a), (Ia-7a), and (Ia-8a)], R₁,when present [i.e., when specifically depicted in the formula], isselected from hydrogen, halogen, and cyano. In another embodiment forformula (Ia-1) through (Ia-8a), R₁, when present, is selected fromhydrogen, fluoro, and cyano. In another embodiment for formula (Ia-1)through (Ia-8a), R₁, when present, is hydrogen or fluoro. In anotherembodiment for formula (Ia-1) through (Ia-8a), R₁, when present, ishydrogen. In another embodiment for formula (Ia-1) through (Ia-8a), R₁,when present, is fluoro.

In another embodiment for formula (Ia-1) through (Ia-8a), R₄, whenpresent, is selected from:

In another embodiment for formula (Ia-1) through (Ia-8a), R₄, whenpresent, is selected from:

In another embodiment for formula (Ia-1) through (Ia-8a), R₄, whenpresent, is selected from:

In another embodiment for formula (Ia-1) through (Ia-8a), R₅, whenpresent, is hydrogen, halogen, C₁-C₄ alkyl, or C₁-C₄ halogenoalkyl. Inanother embodiment for formula (Ia-1) through (Ia-8a), R₅, when present,is hydrogen, C₁-C₄ alkyl, or C₁-C₄ halogenoalkyl. In another embodimentfor formula (Ia-1) through (Ia-8a), R₅, when present, is hydrogen,methyl, or trifluoromethyl.

In another embodiment for formula (Ia-1) through (Ia-8a), R₇, whenpresent, is hydrogen.

In another embodiment for formula (Ia-1) through (Ia-8a), Q is selectedfrom a 6-membered aryl and a 5- or 6-membered heteroaryl having 1, 2, or3 heteroatoms independently selected from N, O, and S, wherein the aryland heteroaryl are optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from halogen, C₁-C₄ halogenoalkyl,and C₁-C₄ alkoxy. In another embodiment for formula (Ia-1) through(Ia-8a), Q is selected from a 6-membered aryl optionally substituted by1, 2, 3, 4, or 5 substituents independently selected from halogen.

In another embodiment for formula (Ia-1) through (Ia-8a), Q is selectedfrom:

In another embodiment for formula (Ia-1) through (Ia-8a), Q is selectedfrom:

In another embodiment for formula (Ia-1) through (Ia-8a),

-   -   X₁, X₂, X₃, X₄, X₅, X₆, when present, are as defined in the        Summary;    -   R₁, when present, is selected from hydrogen, halogen, and cyano;    -   R₄, when present, is selected from:

-   -   R₅, when present, is selected from hydrogen, methyl, and        trifluoromethyl;    -   R₇, when present, is hydrogen; and    -   Q is selected from:

-   -   or a salt thereof.

In another embodiment for formula (Ia-1) through (Ia-8a),

-   -   X₁, X₂, X₃, X₄, X₅, X₆, when present, are as defined in the        Summary;    -   R₁, when present, is selected from hydrogen, halogen, and cyano;    -   R₄, when present, is selected from:

-   -   R₅, when present, is selected from hydrogen;    -   R₇, when present, is hydrogen; and    -   Q is selected from:

-   -   or a salt thereof.

In another embodiment, the compound of formula (I), or a salt thereof,has formula (Ia-5),

wherein R₁, R₄, and Q are as defined in the Summary. Preferably, R₁ ishydrogen, halogen, or cyano. More preferably, R₁ is hydrogen or fluoro.Preferably, R₄ is 4-morpholino or dimethylamino. Preferably, Q is a6-membered aryl optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting ofhalogen, cyano, nitro, hydroxyl, C₁-C₄ alkyl, C₁-C₄ halogenoalkyl, C₁-C₄alkoxy, C₃-C₆ cycloalkyl, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—NH(C₃-C₆ cycloalkyl), —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄alkyl), —SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,—S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl, wherein the 6- or10 membered aryl is optionally fused with a 4- to 7-memberedheterocycloalkyl having 1 or 2 heteroatoms selected from the group O, S,and N and wherein the carbons of the heterocycloalkyl are optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup halogen, cyano, nitro, hydroxyl, oxo, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl),and —N(C₁-C₄ alkyl)₂ and any N in the heterocycloalkyl is, valencypermitting, substituted with a substituent selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl. Preferably, Qis 6-membered aryl substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from halogen, C₁-C₄ alkyl, C₁-C₄ halogenoalkyl,and cyano. Preferably, Q is selected from:

The compounds of the invention can be prepared by a variety ofprocedures, some of which are described below. All substituents, unlessotherwise indicated, are as previously defined.

The products of each step can be recovered by conventional methodsincluding extraction, evaporation, precipitation, chromatography,filtration, trituration, crystallization, and the like. The proceduresmay require protection of certain groups, for example hydroxyl, thiol,amino, or carboxyl groups to minimize unwanted reactions. The selection,use, and removal of protecting groups are well known and appreciated asstandard practice, for example T. W. Greene and P. G. M. Wuts inProtective Groups in Organic Chemistry (John Wiley and Sons, 1991).

As used herein: AcOH refers to acetic acid; aq. refers to aqueous, brrefers to broad, CH₃CN refers to acetonitrile, CH₂Cl₂ refers tomethylene chloride, d refers to doublet, dd refers to doublet ofdoublet, DIPEA refers to N-diisopropylethylamine, DMA refers toN,N-dimethylacetamide, DMF refers to N,N-dimethylformamide, DMSO refersto dimethylsulfoxide, ee: refers to enantiomeric excess, eq. refers toequivalent, ES refers to electrospray ionization, EtOAc refers to EtOAc,EtOH refers to EtOH, HATU refers to1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, HPLC refers to high performance liquidchromatography, iPrOH refers to isopropanol, J refers to couplingconstant, KOAc refers to potassium acetate, K₂CO₃ refers to potassiumcarbonate, LCMS refers to liquid chromatography-mass spectrometry, m/z:refers to mass-to-charge ratio, M refers to molarity, m refers tomultiplet, MeOH refers to mEtOH, min. refers to minutes, NaHCO₃ refersto sodium bicarbonate, Na₂CO₃ refers to sodium carbonate, NEt₃ refers totriethylamine, NMR refers to nuclear magnetic resonance, NMP refers toN-methylpyrrolidone, PEG refers to polethyleneglycol, q refers toquartet, quint refers to quintet, rt refers to rt, R_(t) refers toretention time, s refers to singlet, sat. refers to saturated, T refersto temperature, t refers to triplet, td refers to triplet of doublets,THF refers to THF, wt refers to weight, and δ refers to chemical shift.

Scheme A depicts the reaction of a compound of formula (1) and acompound of formula (2) to give a compound of formula (Ia). The depictedcompound of formula (1) is one in which the group A₁ is a hydroxylgroup, or an activating groups as is discussed below, and Q, M, X₁, X₂,X₃, X₄, X₅, and X₆ are as desired in the final compound of formula (Ia)or a group that gives rise to Q, M, X₁, X₂, X₃, X₄, X₅, and X₆ asdesired in the final compound of formula (Ia). For example, a compoundof formula (1) can be one in which the depicted group “Q” is a halogenwhich is further elaborated, in a subsequent step, not shown, to give acompound in which Q is as defined in formula (Ia). Also, for example, acompound in which M is O can be further elaborated to compound in M is Sor in which M is NR₁₃. The preparation of such compounds of formula (1)is readily appreciated in the art. A compound of formula (2) is one inwhich R₇, n, Y₁, Y₂, Z₁, Z₂, Z₃, and Z₄ are as desired in the finalproduct of formula (Ia) or a group that gives rise to R₇, Y₁, Y₂, Z₁,Z₂, Z₃, and Z₄ as desired in the final product of formula (Ia). Thepreparation of such compounds of formula (2) is readily appreciated inthe art.

As mentioned above, Scheme A depicts the reaction of a compound offormula (1) using a compound of formula (2) to give a compound offormula (Ia). Typical groups A₁ are hydroxyl or a leaving group, such aschloro, bromo, or imidazolyl, an activating moiety, a mixed anhydride ofanother carboxylic acid, such as formic acid, acetic acid, or representsthe other part of a symmetrical anhydride formed from two compounds offormula (1). For example, standard amide forming conditions can be used,such as those using coupling agents, including those used in peptidecouplings, such as 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU),dicyclohexylcarbodiimide (DCC), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl. If necessary ordesired, an additive such as 4-(dimethylamino)pyridine,1-hydroxybenzotriazole, and the like may be used to facilitate thereaction. Such reactions are generally carried out using a base, such asN-methylmorpholine or NEt₃, in a wide variety of suitable solvents suchas CH₂Cl₂, DMF, NMP, DMA, THF, and the like. Such reactions are wellunderstood and appreciated in the art.

It will be recognized by one of ordinary skill in the art that acompound of formula (Ia) can be elaborated in a variety of ways to giveother compounds of formula (Ia). Such reactions include hydrolysis,oxidation, reduction, alkylation, arylation (including heteroarylgroups) amidations, sulfonations, and the like.

Also, in an optional step, not shown, the compounds of formula (Ia) canbe converted to salts by methods well known and appreciated in the art.

Scheme B depicts the reaction of a compound of formula (3) and acompound of formula (4) to give a compound of formula (Ib). The depictedcompound of formula (3) Q, R₇, X₁, X₂, X₃, X₄, X₅, and X₆ are as desiredin the final compound of formula (I) or a group that gives rise to Q,R₇, X₁, X₂, X₃, X₄, X₅, and X₆ as desired in the final compound offormula (Ib). For example, a compound of formula (3) can be one in whichthe depicted group “Q” is a halogen which is further elaborated, in asubsequent step, not shown, to give a compound in which Q is as definedin formula (Ib). The preparation of such compounds of formula (3) isreadily appreciated in the art. A compound of formula (4) is one inwhich is one in which the group A₂ is a carboxy group, or an activatinggroups as is discussed below, and n, Y₁, Y₂, Z₁, Z₂, Z₃, and Z₄ are asdesired in the final product of formula (Ib) or a group that gives riseto Y₁, Y₂, Z₁, Z₂, Z₃, and Z₄ as desired in the final product of formula(Ib). The preparation of such compounds of formula (4) is readilyappreciated in the art.

As mentioned above, Scheme B depicts the reaction of a compound offormula (3) in which using a compound of formula (4) to give a compoundof formula (Ib). Typical groups A₂ are carboxy or an acid chloride oracid bromide, or imidazide, an activating moiety, a mixed anhydride ofanother carboxylic acid, such as formic acid, acetic acid, or representsthe other part of a symmetrical anhydride formed from two compounds offormula (4) in which A₂ is carboxy derivative or another activatedmoiety. Such reactions are generally carried out using a base, such asN-methylmorpholine or triethylamine, in a wide variety of suitablesolvents such as CH₂Cl₂, DMF, N-methylpyrrolidone (NMP), DMA, THF, andthe like. As is well known, a compound of (Ib) in which M is O can befurther elaborated to compound in M is S or in which M is NR₁₃.

Scheme C depicts the reaction of a compound of formula (5) and acompound of formula (6) to give a compound of formula (Ib). The depictedcompound of formula (5) is the same as the a compound of formula (3)described in Scheme B. A compound of formula (6) is one in which is onein which the depicted R₇ and n, Y₁, Y₂, Z₁, Z₂, Z₃, and Z₄ are asdesired in the final product of formula (Ib) or a group that gives riseto the depicted R₇, and Y₁, Y₂, Z₁, Z₂, Z₃, and Z₄ as desired in thefinal product of formula (Ib). The preparation of such compounds offormula (6) is readily appreciated in the art. The formation ofunsymmetrical ureas is well known using phosgene, carbonyldiimidazole,isopropenyl carbamates, and optionally substituted phenoxy carbonylhalides, such as p-nitrophenoxycarbonyl chloride.

Such reactions are generally carried out in a sequential manner byadding phosgene, carbonyldiimidazole, isopropenyl carbamates, andoptionally substituted phenoxycarbonyl halides to either a compound offormula (5) or a compound of formula (6) using a base, such asN-methylmorpholine or triethylamine, in a wide variety of suitablesolvents such as CH₂Cl₂, DMF, N-methylpyrrolidone (NMP), DMA, THF, andthe like. Then the other of compound (5) or compound (6) is added.

It will be recognized by one of ordinary skill in the art that inSchemes B and C a compound of formula (Ib) can be elaborated in avariety of ways to give other compounds of formula (Ib). Such reactionsinclude hydrolysis, oxidation, reduction, alkylation, arylation(including heteroaryl groups) amidations, sulfonations, and the like. Asis well known, a compound of (Ib) in which M is O can be furtherelaborated to compound in M is S or in which M is NR₁₃.

Also, in an optional step, not shown, the compounds of formula (Ib) canbe converted to salts by methods well known and appreciated in the art.

The following examples are intended to be illustrative and non-limiting,and represent specific embodiments of the present invention.

Analyses methods A and B were performed using an Agilent 1200 InfinitySeries Liquid Chromatography (LC) system, consisting of a 1260 HiPdegasser (G4225A), 1260 Binary Pump (G1312B), 1290 auto-sampler(G4226A), 1290 thermo-stated column compartment (G1316C) and a 1260Diode Array Detector (G4212B) coupled to an Agilent 6150 singlequadrupole mass spectrometry (MS) detector. The injection volume was setto 1 μL by default. The UV (DAD) acquisition was performed at 40 Hz,with a scan range of 190-400 nm (by 5 nm step). A 1:1 flow split wasused before the MS detector. The MS was operated with an electro-sprayionization source (ESI) in both positive & negative ion mode. Thenebulizer pressure was set to 50 psi, the drying gas temperature andflow to 350° C. and 12 L/min respectively. The capillary voltages usedwere 4000V in positive mode and 3500V in negative mode. The MSacquisition range was set to 100-800 m/z with a step size of 0.2 m/z inboth polarity modes. Fragmentor voltage was set to 70 (ESI+) or 120(ESI−), Gain to 0.40 (ESI+) or 1.00 (ESI−) and the ion count thresholdto 4000 (ESI+) or 1000 (ESI−). The overall MS scan cycle time was 0.15s/cycle. Data acquisition was performed with Agilent Chemstationsoftware.

Method A: Analyses were carried out on a Phenomenex Gemini-NX C18 columnof 50 mm length, 2.1 mm internal diameter and 3 μm particle size. Themobile phase used was: A1=Water with 0.1% formic acid/B1=CH₃CN with 0.1%formic acid. The run was performed at a temperature of 50° C. and a flowrate of 1.2 mL/min, with a gradient elution from 5% to 95% (B1) over 1.5min followed by a 0.5 min hold at 95% (B1).

Method B: Analyses were carried out on a Waters)(Bridge C18 column of 50mm length, 2.1 mm internal diameter and 3.5 μm particle size. The mobilephase used was: A2=Water with 10 mM ammonium bicarbonate, adjusted at pH9 with ammonium hydroxide/B2=CH₃CN. The run was performed at atemperature of 50° C. and a flow rate of 1.2 mL/min, with a gradientelution from 5% to 95% (B2) over 1.5 min followed by a 0.5 min hold at95% (B2).

Analyses methods C and D were performed using a Waters Acquity UPLCLiquid Chromatography (LC) system, coupled to an Waters SQ Detector 2single quadrupole mass spectrometry (MS) detector. The UV (DAD)acquisition was performed with a scan range of 200-400 nm (by 1.2 nmresolution). The MS was operated with an electro-spray ionization source(ESI) in both positive & negative ion mode. Capillary Voltage 3.50(kV),Cone Voltage 35(V), and Desolvation Temperature of 550° C. Desolvationgas flow 1000 (L/Hr), Cone gas flow 50 (L/Hr). The MS acquisition rangewas set to 100-1500 m/z. MS scan cycle time was 0.5 s. Data acquisitionwas performed with Waters Masslynx software.

Method C: Analyses were carried out on an Acquity UPLC BEH C18 column of50 mm length, 2.1 mm internal diameter and 1.7 μm particle size. Themobile phase used was: A1=Water with 0.1% formic acid/B1=CH₃CN with 0.1%formic acid. The injection volume was 0.1 μL. The run was performed at atemperature of 40° C. and a flow rate of 0.6 mL/min, with a gradientelution. Method info (Time (min) and B %): 0-5; 0.3-5; 2.5-95; 3.7-95;4-5; 4.6-5.

Method D: Analyses were carried out on an Acquity UPLC BEH C18 column of50 mm length, 2.1 mm internal diameter and 1.7 μm particle size. Themobile phase used was: A1=Water with 10 mM Ammonium acetate/B1=CH₃CNwith 0.1% formic acid. The injection volume was 0.1 μL. The run wasperformed at a temperature of 45° C. and a flow rate of 0.5 mL/min, witha gradient elution. Method info (Time (min) and A %): 0-98; 0.3-98;3.2-2; 4.4-2; 4.7-98.

Example 1.1N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl]-2,3-dihydro-1,4-benzoxazine-4-carboxamide

To a stirred solution of 8-bromoquinolin-4-ol (2 g, 8.82 mmol) inpropionic acid (20 mL, 265 mmol) at 100° C. was added nitric acid (1 mL,16 mmol) slowly over 5 min. The reaction was heated to 125° C. and leftto stir for 45 min. The reaction was then allowed to cool to rt, causingthe product to precipitate. The solid was collected by filtration andwashed with water (3×10 mL), iPrOH (10 mL), isohexane (10 mL), and thendried in the vacuum oven for 1 hour to give8-bromo-3-nitro-quinolin-4-ol. LCMS (method B): R_(t)=0.54 min, m/z=269[M+H]⁺.

To a solution of 8-bromo-3-nitro-quinolin-4-ol (1.52 g, 5.37 mmol) wasadded POCl₃ (10 mL, 107 mmol). The suspension was heated to reflux andstirred for 2 hours. The reaction mixture was allowed to cool to rt, andleft to stand overnight. The reaction mixture was concentrated in vacuo(azeotroping with toluene) to give 8-bromo-4-chloro-3-nitro-quinolinewhich was used directly in the next step without further purification.

To a solution of 8-bromo-4-chloro-3-nitro-quinoline (2.32 g, 5.38 mmol)in THF (30 mL) was slowly added dimethylamine (2 M in THF, 7 mL, 14mmol). The reaction was left to stir at rt for 1.5 hour. The reactionmixture was partitioned between EtOAc and sat. aq. NaHCO₃ (50 mL ofeach). Brine (50 mL) was added. The layers were separated and the aq.layer was extracted with EtOAc (2×50 mL). The combined organic layerswere concentrated in vacuo to give8-bromo-N,N-dimethyl-3-nitro-quinolin-4-amine. LCMS (method B):R_(t)=1.13 min, m/z=296 [M+H]⁺.

To a solution of 8-bromo-N,N-dimethyl-3-nitro-quinolin-4-amine (505 mg,1.62 mmol), was added (3,5-dichlorophenyl) boronic acid (314 mg, 1.61mmol), tetrakis(triphenylphosphine) palladium(0) (92 mg, 0.08 mmol) andNa₂CO₃ (351 mg, 3.28 mmol). The vial was sealed, then evacuated andback-filled with N₂ three times. 1,4-dioxane (9 mL) was added, followedby water (3 mL) and the reaction was heated to 100° C. in the microwavefor 1 hour. The reaction mixture was partitioned between EtOAc and sat.aq. NaHCO₃ (50 mL of each). The layers were separated and the aq. layerwas extracted with EtOAc (2×25 mL). The combined organic layers wereconcentrated in vacuo and the residue was purified by columnchromatography to give8-(3,5-dichlorophenyl)-N,N-dimethyl-3-nitro-quinolin-4-amine. LCMS(method B): R_(t)=1.57 min, m/z=362 [M+H]⁺.

To a stirred suspension of8-(3,5-dichlorophenyl)-N,N-dimethyl-3-nitro-quinolin-4-amine (401 mg,1.05 mmol) in THF (5 mL), EtOH (5 mL) and water (2.5 mL) was added iron(184 mg, 3.23 mmol) and NH₄Cl (168 mg, 3.13 mmol). The reaction washeated to 75° C. and left to stir for 45 min. The reaction was allowedto cool to rt, then partitioned between sat. aq. NaHCO₃ and EtOAc (25 mLof each). The mixture was filtered through Celite® (washing with EtOAc),and the layers of the filtrate were separated. The aq. layer wasextracted with EtOAc (2×25 mL), and the combined organic layers wereconcentrated in vacuo. The residue was purified by column chromatographyto give 8-(3,5-dichlorophenyl)-N4,N4-dimethyl-quinoline-3,4-diamine.LCMS (method B): R_(t)=1.48 min, m/z=363.2 [M+H]⁺.

To a stirred solution of 4-nitrophenyl chloroformate (88 mg, 0.42 mmol)in THF (2 mL) at 0° C. under N2-atmosphere was added a solution of8-(3,5-dichlorophenyl)-N⁴,N⁴-dimethyl-quinoline-3,4-diamine (148 mg,0.42 mmol) in THF (2.5 mL) dropwise over 2 min. The reaction was left tostir at 0° C. for 30 min. The reaction solution was used directly in thenext step.

To the reaction mixture was added 3,4-dihydro-2H-1,4-benzoxazine (71 mg,0.51 mmol) and NEt₃ (132 μL, 0.94 mmol) in THF (0.5 mL). The reactionwas stirred at rt overnight. The reaction mixture was partitionedbetween sat. aq. NaHCO₃ and CH₂Cl₂ (20 mL of each). The layers wereseparated and the aq. layer was extracted with CH₂Cl₂ (2×20 mL). Thecombined organic layers were passed through Celite®, and concentrated invacuo. The crude product was purified by column chromatography to affordthe title compound. LCMS (method B): R_(t)=1.62 min, m/z=493.0 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ [ppm]: 9.95 (s, 1H), 9.13 (s, 1H), 7.91(quint, J=4.8 Hz, 1H), 7.55 (d, J=2 Hz, 1H), 7.53 (d, J=5.2 Hz, 1H),7.43 (dd, J=1.6, 8.4 Hz, 1H), 7.38 (t, J=2 Hz, 1H), 7.17 (m, 1H), 7.01(m, 2H), 4.36 (t, J=4.4 Hz, 2H), 4.02 (t, J=4.8 Hz, 2H), 2.9 (s, 6H).

Example 2.18-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide

A mixture of 2-chloro-3-fluoro-pyridine-4-carboxylic acid (10.1 g, 56.3mmol) and SOCl₂ (40 mL, 547 mmol) was heated at 80° C. for 2 hours. Thereaction was allowed to cool to rt, and concentrated in vacuo. It wasused directly in the next step: toluene (145 mL) and NEt₃ (9.8 mL, 70mmol) were added followed by ethyl 3-(dimethylamino)-prop-2-enoate (10.2g, 69.6 mmol). The reaction was heated at 80° C. and stirred for 45 min.The mixture was allowed to cool to rt, and filtered through Celite®(washing with EtOAc). The filtrate was concentrated in vacuo, and theresidue was partitioned between EtOAc and aq. 2M HCl (150 mL of each).The layers were separated and the aq. layer was extracted with EtOAc(150 mL). The combined organic layers were dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to give ethyl2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-(dimethylamino)-prop-2-enoate.LCMS (method B): R_(t)=0.86 min, m/z=301.00 [M+H]⁺. To a solution ofethyl2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-(dimethylamino)-prop-2-enoate(188 mg, 0.59 mmol) in diethyl ether (2.4 mL) and EtOH (0.6 mL) wasadded 4-methoxybenzylamine (94 μL, 0.71 mmol). The reaction mixture wasstirred at rt for 15 min, forming a precipitate. The reaction mixturewas concentrated in vacuo to give a residue. The residue was trituratedwith cyclohexane to give ethyl2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-[(4-methoxyphenyl)methyl-amino]-prop-2-enoate. LCMS (method B): R_(t)=1.21 min, m/z=393[M+H]⁺.

To a solution of ethyl2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-[(4-methoxyphenyl)methyl-amino]-prop-2-enoate (214 mg, 518 μmol) in DMF (2.6 mL) was addedK₂CO₃ (230 mg, 1.66 mmol) at rt. The reaction mixture was heated at 40°C. and left to stir for 2 hours. After cooling down to rt, the reactionmixture was poured into ice water (20 mL), forming a fine precipitate.The precipitate was dissolved in EtOAc (20 mL), and the layers wereseparated. The aq. layer was extracted with EtOAc (2×10 mL) and thecombined organic layers were washed with water (20 mL), dried overanhydrous MgSO₄, filtered, and concentrated in vacuo to give ethyl8-chloro-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate. LCMS (method B):R_(t)=1.01 min, m/z=373 [M+H]⁺.

(3,5-Dichlorophenyl) boronic acid (110 mg, 0.56 mmol) was mixed with1,1′-bis(diphenylphosphino) ferrocene-Pd(II).CH₂Cl₂ complex and Na₂CO₃(100 mg, 0.93 mmol). The vial was sealed, then evacuated and back-filledwith N2. Then, ethyl 8-chloro-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate (186 mg, 0.47 mmol) in1,4-dioxane (2.4 mL, 28 mmol) was added, followed by water (0.8 mL) andthe reaction mixture was heated at 100° C. in the microwave for 1 hour.The reaction mixture was filtered through Celite® (washing with EtOAc).The filtrate was washed with water (20 mL), dried over anhydrous MgSO₄,filtered, and concentrated in vacuo, then purified by columnchromatography to give ethyl 8-(3,5-dichlorophenyl)-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate. LCMS (methodB): R_(t)=1.30 min, m/z=483 [M+H]⁺.

To a solution of ethyl8-(3,5-dichlorophenyl)-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate(877 mg, 1.72 mmol) in CH₂Cl₂ (9 mL) was added anisole (1 mL, 1.74mmol), followed by TFA (2.5 mL, 33 mmol). The resulting reaction mixturewas stirred at rt for 1 hour, before being concentrated in vacuo. Amixture of sat. aq. NaHCO₃ and EtOAc (25 mL of each) was added to thecrude product and the resulting suspension was stirred vigorously for 15min. The precipitate was isolated by filtration (washing with water,then EtOAc), and dried in a vacuum oven to give ethyl8-(3,5-dichlorophenyl)-4-hydroxy-1,7-naphthyridine-3-carboxylate. LCMS(method B): R_(t)=0.9 min, m/z=363 [M+H]⁺.

To a stirring suspension of ethyl8-(3,5-dichlorophenyl)-4-hydroxy-1,7-naphthyridine-3-carboxylate (61 mg,0.13 mmol) in CH₂Cl₂ (2 mL) was added oxalyl chloride (17 μL, 192 μmol)followed by DMF (1 μL, 13 μmol) and the resulting mixture was left tostir at rt for 45 min. The reaction was quenched by the addition of asat. aq. NaHCO₃ solution (5 mL), and the mixture was partitioned betweenwater and CH₂Cl₂ (10 mL of each). The layers were separated and the aq.layer was extracted with CH₂Cl₂. The combined organic layers were driedover anhydrous MgSO₄, filtered, and concentrated in vacuo to give ethyl4-chloro-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxylate. LCMS(method B): R_(t)=1.6 min, m/z=381 [M+H]⁺.

To a microwave vial was added ethyl4-chloro-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxylate (59 mg,0.12 mmol) and dimethylamine.HCl (17 mg, 0.2 mmol) in 1,4-dioxane (0.5mL). The vial was sealed, DIPEA (73 μL, 0.41 mmol) was added and thereaction mixture was heated in the microwave at 100° C. for 30 min. Themixture was diluted with EtOAc (10 mL), washed with a sat. aq. NaHCO₃solution (10 mL), and brine (10 mL), dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to give ethyl8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylate.LCMS (method B): R_(t)=1.5 min, m/z=390 [M+H]⁺.

To a stirring solution of ethyl8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylate(556 mg, 1.35 mmol) in THF (14 mL) was added a solution of lithiumhydroxide (99 mg, 4.05 mmol) in water (4.5 mL) and MeOH (4.5 mL). Thereaction mixture was heated at 40° C. for 2 hours and left to stir at rtovernight. Then, the mixture was concentrated in vacuo, and the residuewas taken up in water (25 mL). The aq. layer was washed with EtOAc (25mL), then adjusted to pH 4 by the addition of aq. 2 M HCl, forming asuspension. The precipitate was isolated by filtration, and dried in thevacuum oven overnight to give8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylicacid as a solid. LCMS (method B): R_(t)=0.78 min, m/z=362 [M+H]⁺.

At rt, under N2-atmosphere, to a solution of3,4-dihydro-2H-1,4-benzoxazine (504 mg, 3.73 mmol) in EtOH (4 mL), wasadded sodium nitrite (309 mg, 4.48 mmol) in water (1.6 mL). The mixturewas then cooled to 0° C. Conc. HCl (0.39 mL, 4.7 mmol) was addeddropwise to the reaction at 0° C. The reaction was then stirred at 0° C.for 15 min.

A solution of sodium hydroxide (1.43 g, 35.87 mmol) in water (3.7 mL)was added at 0° C. followed by sodium hydrosulfite (2.40 g, 11.75 mmol).The resulting suspension was heated to 90° C. for 2 hours, then it wascooled to rt.

The reaction was diluted with water (30 mL) and then extracted withtoluene (30 mL) and EtOAc (15 mL). The combined organic layers wereseparated and concentrated in vacuo. The residue was purified by columnchromatography to afford 2,3-dihydro-1,4-benzoxazin-4-amine, as a paleyellow oil (354 mg). LCMS (method B) R_(t)=0.63 min, m/z=151 [M+H]⁺. Toa stirring suspension of8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylicacid (158 mg, 0.41 mmol) in DMF (5 mL) was added NEt₃ (0.25 mL, 1.8mmol), followed by 2,3-dihydro-1,4-benzoxazin-4-amine (79 mg, 0.501mmol) and PyBOP (341 mg, 0.64 mmol). The reaction was left to stir at rtunder N2-atmosphere for 48 hours. The reaction was diluted with brine(25 mL) and extracted with CH₂Cl₂ (3×15 mL). The combined organic layerswere separated and concentrated in vacuo. The residue was purified bycolumn chromatography to afford the title compound. LCMS (method B)R_(t)=1.35 min, m/z=494 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.7(s, 1H), 8.90 (s, 1H), 8.67 (d, J=4.4 Hz, 1H), 8.1 (m, 2H), 7.75 (t, J=2Hz, 1H), 7.03 (dd, J=8, 1.2 Hz, 1H), 6.85 (td, J=2, 8 Hz, 1H), 6.69-6.78(m, 2H), 4.38 (t, J=4.4 Hz, 2H), 3.68 (s, 2H), 3.13 (s, 6H).

The following compounds were prepared analogously by the methodology ofExample 2.1:

Ex. Name Structure 2.2 8-(3,5-dichlorophenyl)-N-(3,4-dihydro-2H-quinolin-1- yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide

2.3 8-(3,5-dichlorophenyl)-N- (2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7- naphthyridine-3-carboxamide

2.4 N-(2,3-dihydro-1,4- benzoxazin-4-yl)-4- morpholino-8-(2,3,5-trifluorophenyl)-1,7- naphthyridine-3-carboxamide

2.5 N-(2,3-dihydro-1,4- benzoxazin-4-yl)-4- [methoxy(methyl)amino]-8-(2,3,5-trifluorophenyl)- 1,7- naphthyridine-3-carboxamide

2.6 8-[3-chloro-5- (trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin- 4-yl)-4-morpholino-1,7-naphthyridine-3-carboxamide

2.7 N-(2,3-dihydro-1,4- benzoxazin-4-yl)-4- morpholino-8-(2,3-dichlorophenyl)-1,7- naphthyridine-3-carboxamide

2.8 8-(3,5-dichloro-4-fluoro- phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4- morpholino-1,7- naphthyridine-3-carboxamide

2.9 8-(5-chloro-3-pyridyl)-N- (2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7- naphthyridine-3-carboxamide

2.10 N-(2,3-dihydro-1,4- benzoxazin-4-yl)-4- thiomorpholino-8-(2,3,5-trifluorophenyl)-1,7- naphthyridine-3-carboxamide

2.11 N-(2,3-dihydro-1,4- benzoxazin-4-yl)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-8- (2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide

2.12 N-(2,3-dihydro-1,4- benzoxazin-4-yl)-4- morpholino-8-(3,4,5-trifluorophenyl)-1,7- naphthyridine-3-carboxamide

Example 3.18-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dim ethylamino)-1,5-naphthyridine-3-carboxamide

Thionyl chloride (15 mL, 205 mmol) was added to3,4-dichloropyridine-2-carboxylic acid (3.96 g, 20.6 mmol) and thereaction mixture was heated to 80° C. for 1 hour. The reaction wasallowed to cool to rt, and concentrated in vacuo to give3,4-dichloropyridine-2-carbonyl chloride which was used in the next stepwithout further purification.

To a stirring solution of 3,4-dichloropyridine-2-carbonyl chloride (20.6mmol, 4.76 g) in toluene (50 mL) was added NEt₃ (3.5 mL, 25 mmol)followed by ethyl 3-(dimethylamino)prop-2-enoate (3.6 mL, 25 mmol). Thereaction was stirred at rt overnight. The reaction was filtered throughCelite® (washing with EtOAc). The filtrate was concentrated in vacuo,and the residue was partitioned between EtOAc and aq. 1M HCl (100 mL ofeach). The layers were separated, and the aq. layer was extracted withEtOAc (50 mL). The combined organic layers were concentrated in vacuo togive ethyl2-(3,4-dichloropyridine-2-carbonyl)-3-(dimethylamino)prop-2-enoate. LCMS(method B) R_(t)=0.88 min, m/z=317.0 [M+H]⁺.

To a stirring solution of ethyl2-(3,4-dichloropyridine-2-carbonyl)-3-(dimethylamino) prop-2-enoate(5.58 g, 12.7 mmol) in diethyl ether (50 mL) and EtOH (12 mL) was added4-methoxybenzylamine (1.9 mL, 14 mmol). The reaction was left to stir atrt for 2 hours. The reaction mixture was diluted with water (100 mL).The layers were separated and the aq. layer was extracted with CH₂Cl₂(3×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give ethyl2-(3,4-dichloropyridine-2-carbonyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate.

Ethyl2-(3,4-dichloropyridine-2-carbonyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate(5.92 g, 9.40 mmol) was dissolved in DMF (24 mL). K₂CO₃ (4.0 g, 28.9mmol) was added and the mixture was stirred at 90° C. for 6 hours. Thereaction mixture was cooled down to rt, quenched by addition of water(250 mL) and diluted with CH₂Cl₂ (100 mL). The layers were separated andthe aq. layer was extracted with CH₂Cl₂ (2×50 mL). The combined organiclayers were filtered through Celite® and then washed with brine (100mL), dried over anhydrous Na₂SO₄, filtered and reduced to dryness invacuo. The crude material was purified by chromatography (0-6% MeOH inCH₂Cl₂) to give ethyl 8-hydroxy-1-[(4-methoxyphenyl)methyl]-4-oxo-1,5-naphthyridine-3-carboxylate.

Ethyl 8-hydroxy-1-[(4-methoxyphenyl)methyl]-4-oxo-1,5-naphthyridine-3-carboxylate (840 mg, 1.09 mmol) wasdissolved in CH₂Cl₂ (11 mL) and DMF (0.05 mL). To this mixture, oxalylchloride (0.48 mL, 5.5 mmol) was added and the mixture was heated toreflux for 3 hours. The reaction mixture was cooled down and wasquenched by addition of sat. aq. NaHCO₃ solution (50 mL). The layerswere separated and the aq. layer was extracted with CH₂Cl₂ (2×25 mL).The combined organic layers were reduced in vacuo to give ethyl4,8-dichloro-1,5-naphthyridine-3-carboxylate.

Ethyl 4,8-dichloro-1,5-naphthyridine-3-carboxylate (950 mg, 2.21 mmol)was dissolved in THF (5 mL). To this solution, dimethylamine (2 mol/L)in THF (1.1 mL, 2.2 mmol, 2 M) was added dropwise and the mixture wasstirred at rt for 30 min. The crude reaction mixture concentrated andthe residue was purified by column chromatography (20-50% EtOAc incyclohexane) to give ethyl8-chloro-4-(dimethylamino)-1,5-naphthyridine-3-carboxylate. LCMS (methodB) R_(t)=1.07 min, m/z=280.0 [M+H]⁺.

Ethyl 8-chloro-4-(dimethylamino)-1,5-naphthyridine-3-carboxylate (315mg, 0.93 mmol) was dissolved in 1,4-dioxane (3 mL) and water (1 mL). Tothis mixture, 1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (40 mg, 0.048 mmol) was added(3,5-dichlorophenyl)boronic acid (215 mg, 1.13 mmol) and Na₂CO₃ (300 mg,2.83 mmol). The mixture was submitted to microwave irradiation for 1hour at 100° C. The crude reaction mixture was concentrated and theresidue was purified by column chromatography (5-40% EtOAc incyclohexane) to give ethyl8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxylate.LCMS (method B) R_(t)=1.56 min, m/z=390.0 [M+H]⁺.

To a stirring solution of ethyl8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxylate(272 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was added lithium hydroxide(32 mg, 1.34 mmol) in water (2 mL). The reaction was heated to 100° C.overnight. Then, the reaction mixture was cooled down to rt. Thereaction mixture was quenched by addition of water (50 mL) and EtOAc (50mL). pH was adjusted to pH=4 with 2M HCl. The layers were separated andthe aq. layer was extracted with EtOAc (2×50 mL). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andreduced in vacuo to give8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxylicacid. LCMS (method B) R_(t)=0.82 min, m/z=362.0 [M+H]⁺.

A mixture of 2,3-dihydro-1,4-benzoxazin-4-amine (0.115 g, 0.73 mmol) andPyBOP (0.63 g, 1.21 mmol) was placed under N2-atmosphere and treatedwith a solution of8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxylicacid (0.24 g, 0.67 mmol) in THF (3 mL) followed by NEt₃ (0.42 mL, 3mmol). The resulting reaction mixture was allowed to stir at rt over 48hour. The reaction mixture was quenched by addition of sat. aq. NaHCO₃solution (100 mL) and diluted with CH₂Cl₂ (50 mL). The layers wereseparated and the aq. layer was extracted with CH₂Cl₂ (2×25 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andthen reduced in vacuo. The crude product was purified by columnchromatography (10-50% EtOAc in cyclohexane) to afford the titlecompound. LCMS (method B) R_(t)=1.39 min, m/z=494.0 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ [ppm]: 9.62 (s, 1H), 9.24 (s, 1H), 8.96 (d, J=4.4 Hz, 1H),7.59 (m, 3H), 7.47 (t, J=2 Hz, 1H), 6.79-6.95 (m, 4H), 4.50 (t, J=4.4Hz, 2H), 3.74 (t, J=4.8 Hz, 2H), 3.35 (s, 6H).

The following compounds were prepared analogously by the methodology ofExample 3.1:

Ex. Name Structure 3.2 8-(2,3-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4- (dimethylamino)-1,5-naphthyridine-3-carboxamide

3.3 8-(3,5-dichlorophenyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,5- naphthyridine-3-carboxamide

3.4 N-(2,3-dihydro-1,4-benzoxazin- 4-yl)-4-morpholino-8-(2,3,5-trifluorophenyl)-1,5-naphthyridine- 3-carboxamide

Example 4.15-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-1-(dimethylamino)naphthalene-2-carboxamide

A round bottomed flask containing a mixture of1-bromo-5-nitro-naphthalene (1.04 g, 4.13 mmol),(3,5-dichlorophenyl)boronic acid (0.7 g, 3.6 mmol), Na₂CO₃ (0.86 g, 8.10mmol) and [1,1′-bis(diphenylphosphino) ferrocene] dichloropalladium(II)(156 mg, 0.20 mmol) was evacuated and re-filled with N2 three times. Thereaction mixture was treated with 1,4-dioxane (20 mL) and de-gassedwater (6 mL), heated to 80° C. and was allowed to stir for 45 min. Then,the mixture was allowed to cool down to rt before being diluted withwater (40 mL) and extracted with CH₂Cl₂ (3×30 mL). The combined organiclayers were dried over anhydrous MgSO₄, filtered and concentrated invacuo. The crude product was purified by column chromatography and theappropriate fractions were combined and concentrated in vacuo to give1-(3,5-dichlorophenyl)-5-nitro-naphthalene. A mixture of1-(3,5-dichlorophenyl)-5-nitro-naphthalene (928 mg, 2.77 mmol), NH₄Cl(0.47 g, 8.72 mmol) and iron (0.47 g, 8.28 mmol) was placed underN2-atmosphere before being treated with THF (14 mL), EtOH (14 mL) andwater (7 mL). The resulting mixture was heated to 75° C. and was allowedto stir for 45 min. Then, the mixture was allowed to cool down to rtbefore being filtered through Celite® (washed through with CH₂Cl₂). Thefiltrate was concentrated in vacuo, treated with sat. aq. NaHCO₃ (50 mL)and extracted with CH₂Cl₂ (3×25 mL). The combined organic layers weredried over anhydrous MgSO₄, filtered and concentrated in vacuo to give5-(3,5-dichlorophenyl)naphthalen-1-amine. LCMS (method B) R_(t)=1.49min, m/z=288.0 [M+H]⁺.

A solution of 5-(3,5-dichlorophenyl)naphthalen-1-amine (881 mg, 2.60mmol) in DMF (10 mL) was placed under N2-atmosphere, cooled over anice/salt bath to approximately −5° C. and treated withN-bromosuccinimide (474 mg, 2.58 mmol). The resulting reaction mixturewas then treated with sat. aq. NaHCO₃-solution (50 mL) forming a palebrown precipitate. The mixture was extracted with CH₂Cl₂ (3×30 mL) andthe combined organic layers were concentrated in vacuo. The residue waspurified by column chromatography to afford2-bromo-5-(3,5-dichlorophenyl)naphthalen-1-amine. LCMS (method B)R_(t)=1.64 min, m/z=365.8 [M+H]⁺.

A suspension of 2-bromo-5-(3,5-dichlorophenyl)naphthalen-1-amine (0.73g, 1.79 mmol) in formic acid (6 mL, 160 mmol) was placed underN2-atmosphere and treated with formaldehyde solution (37 wt. % in water;110 mmol, 8 mL). The resulting suspension was warmed to 100° C. and wasallowed to stir for 1 hour. The reaction mixture was allowed to cooldown to rt before being quenched by the careful addition of sat. aq.NaHCO₃ solution (60 mL). The mixture was then extracted with CH₂Cl₂(3×20 mL) and the combined organic layers were dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography to afford2-bromo-5-(3,5-dichlorophenyl)-N,N-dimethyl-naphthalen-1-amine. LCMS(method B) R_(t)=1.93 min, m/z=393.8 [M+H]⁺.

A solution of2-bromo-5-(3,5-dichlorophenyl)-N,N-dimethyl-naphthalen-1-amine (532 mg,1.28 mmol) in 1,4-dioxane (10 mL) in a pressure-vessel was treated withMeOH (10 mL), NEt₃ (0.54 mL, 3.9 mmol) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (103 mg, 134 μmol) before being stirredat 100° C. under a CO-atmosphere (50 psi) for 16 hours. Then, thereaction mixture was allowed to cool down to rt, filtered andconcentrated in vacuo. The residue was purified by column chromatographyto afford methyl5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylate. LCMS(method B) R_(t)=1.75 min, m/z=374.0 [M+H]⁺.

A solution of methyl5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylate (421mg, 1.01 mmol) in 1,4-dioxane (15 mL), water (5 mL) and lithiumhydroxide (512 mg, 20.3 mmol) was stirred at 80° C. for 48 hours. Thereaction mixture was allowed to cool down to rt before being treatedwith 2 M HCl (17.5 mL—making the mixture weakly basic). The aq. layerwas extracted with CH₂Cl₂ (3×25 mL). The combined organic layers weredried over anhydrous MgSO₄, filtered and concentrated in vacuo, yielding5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylic acid.LCMS (method B) R_(t)=1.10 min, m/z=358.0 [M−H]⁻.

A mixture of 2,3-dihydro-1,4-benzoxazin-4-amine (0.082 g, 519 μmol) andPyBOP (452 mg, 869 μmol) was placed under N2-atmosphere and treated witha solution of5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylic acid(192 mg, 426 μmol) in THF (3 mL) followed by NEt₃ (0.30 mL, 2.2 mmol).The resulting reaction mixture was allowed to stir at rt overnight. Thereaction mixture was diluted with water (15 mL) and extracted withCH₂Cl₂ (3×15 mL). The combined organic layers were dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The crude product waspurified by column chromatography to give the title compound. LCMS(method B) R_(t)=1.61 min, m/z=492.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ[ppm]: 10.5 (s, 1H), 8.36 (d, J=8.6 Hz, 1H), 7.75 (t, J=2 Hz, 1H),7.64-7.68 (m, 1H), 7.60-7.48 (m, 5H), 6.98 (dd, J=8, 1.4 Hz, 1H),6.86-6.80 (m, 1H), 6.77 (dd, J=8, 1.6 Hz, 1H), 6.73-6.67 (m, 1H), 4.38(t, J=4.3 Hz, 2H), 3.70-3.63 (m, 2H), 2.99 (s, 6H).

Example 5.18-(3,5-dichlorophenyl)-N-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-4-(dimethylamino)quinoline-3-carboxamide

A solution of 2-bromoaniline (7.96 g, 44.9 mmol) and diethyl2-(ethoxymethylene)propanedioate (11 mL, 53.8 mmol) was heated to 125°C. for 1 hour. LCMS (method B) R_(t)=1.28 min, m/z=342.0 [M+H]⁺.Diphenylether (100 mL) was added, and the reaction was heated to 250° C.and left to stir for 48 hours. The reaction was allowed to cool to rt,forming a precipitate. Diethyl ether (100 mL) was added, the precipitatewas isolated by filtration (washing with diethyl ether), and dried invacuo to give ethyl 8-bromo-4-hydroxy-quinoline-3-carboxylate. LCMS(method B) R_(t)=0.69, m/z=296.0 [M+H]⁺.

A suspension of ethyl 8-bromo-4-hydroxy-quinoline-3-carboxylate (2.0 g,6.42 mmol) in CH₂Cl₂ (20 mL) was placed under N2-atmosphere and treatedwith oxalyl chloride (0.60 mL, 6.8 mmol) and DMF (0.02 mL). The reactionmixture was warmed to 50° C. and was allowed to stir for 45 min. Thereaction mixture was allowed to cool to rt then it was concentrated invacuo to give ethyl 8-bromo-4-chloro-quinoline-3-carboxylate. LCMS(method B) R_(t)=1.28 min, m/z=314.0 [M+H]⁺.

Dimethylamine (2 M) in THF (13 mL) was added to ethyl8-bromo-4-chloro-quinoline-3-carboxylate (2.13 g, 6.42 mmol) underN2-atmosphere. The resulting mixture was warmed to 60° C. and wasallowed to stir for 15 min. The reaction mixture was concentrated invacuo before being treated with sat. aq. NaHCO₃ (40 mL) and extractedwith EtOAc (3×30 mL). The combined organic layers were dried overanhydrous MgSO₄ and concentrated in vacuo. The residue was subjected tocolumn chromatography (20-60% EtOAc in cyclohexane) to give ethyl8-bromo-4-(dimethylamino) quinoline-3-carboxylate. LCMS (method B)R_(t)=1.23 min, m/z=323.0 [M+H]⁺.

Under N₂-atmosphere, a reaction mixture of ethyl8-bromo-4-(dimethylamino)quinoline-3-carboxylate (2.22 g, 6.54 mmol),(3,5-dichlorophenyl)boronic acid (1.26 g, 6.61 mmol),bis(diphenylphosphino) ferrocene-Pd(II).CH₂Cl₂ complex (0.27 g, 0.33mmol) and Na₂CO₃ (1.43 g, 13.5 mmol) in 1,4-dioxane (20 mL) and water(10 mL) was heated to 80° C. and was allowed to stir for 30 min. Thereaction mixture was allowed to cool down to rt before being dilutedwith water (70 mL) and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic layers were filtered and concentrated in vacuo. The residue waspurified by column chromatography (0-30% EtOAc in cyclohexane) to giveethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylate.LCMS (method B) R_(t)=1.67 min, m/z=389.0 [M+H]⁺.

A solution of ethyl8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylate (2.82 g,6.17 mmol) in 1,4-dioxane (20 mL) was treated with water (10 mL) andlithium hydroxide (0.44 g, 18.5 mmol). The resulting reaction mixturewas warmed to 100° C. and stirred overnight. The reaction mixture wasallowed to cool down to rt, then it was acidified to pH 2 with 2 M HCland was extracted with EtOAc (3×30 mL). The aq. phase was basified to pH6 and was extracted with 10% MeOH in CH₂Cl₂ (3×30 mL). The organicphases were combined and concentrated in vacuo to give8-(3,5-dichlorophenyl)-4-(dimethylamino) quinoline-3-carboxylic acid.LCMS (method B) R_(t)=0.94 min, m/z=361.0 [M+H]⁺.

To a stirring suspension of 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylic acid (160 mg, 0.35 mmol) in DMF (3.5 mL) wasadded NEt₃ (200 μL, 1.42 mmol), followed by2,3-dihydro-1,4-benzoxazin-4-amine (67 mg, 0.42 mmol) and PyBOP (282 mg,0.53 mmol). The reaction was left to stir at rt under N2-atmosphereovernight. The reaction was diluted with brine and extracted twice withCH₂Cl₂. The crude product was purified by column chromatography elutingwith cyclohexane:EtOAc (0-40% EtOAc) to give the title compound. LCMS(method B) R_(t)=1.47 min, m/z=493.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ[ppm]: 9.04 (s, 1H), 8.4 (s, 1H), 8.20 (dd, J=1.6 Hz, J=8.8 Hz, 1H),7.69-7.71 (m, 1H), 7.58-7.62 (m, 1H), 7.52 (d, J=2 Hz, 2H), 7.4 (t,J=1.6 Hz, 1H), 6.79-6.97 (m, 4H), 4.49 (t, J=4.4 Hz, 2H), 3.74 (t, J=4.4Hz, 2H), 3.19 (s, 6H).

The following compounds were prepared analogously by the methodology ofExample 5.1:

Ex. Name Structure 5.2 8-(2,3-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4- morpholino-quinoline-3- carboxamide

5.3 8-(3,5-dichlorophenyl)-N-(2,3- dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.4 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-7-fluoro-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline- 3-carboxamide

5.5 8-(5-chloro-3-pyridyl)-N-(2,3- dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.6 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide

5.7 8-(3,5-dichlorophenyl)-N-(2,3- dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3- carboxamide

5.8 8-(3,5-difluorophenyl)-N-(2,3- dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3- carboxamide

5.9 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-morpholino-8-pyrimidin-5-yl-quinoline-3-carboxamide

5.10 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-thiomorpholino-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide

5.11 8-[2-chloro-6-(trifluoromethyl)-4- pyridyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino- quinoline-3-carboxamide

5.12 8-(2,6-dichloro-4-pyridyl)-N- (2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.13 8-(3,5-dichloro-2-fluoro-phenyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.14 8-(5-chloro-2-fluoro-3-pyridyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.15 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-8-(2,3,5- trifluorophenyl)quinoline-3- carboxamide

5.16 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-morpholino-8-(2,4,5-trifluorophenyl)quinoline-3- carboxamide

5.17 8-(6-chloropyrazin-2-yl)-N-(2,3- dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.18 8-(4,5-dichloro-3-pyridyl)-N- (2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.19 8-(5-chloro-2,3-difluoro-phenyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.20 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-morpholino-8-(2,3,4,5-tetrafluorophenyl)quinoline-3- carboxamide

5.21 8-(4-chloro-5-fluoro-3-pyridyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.22 8-[4-chloro-6-(trifluoromethyl)-2- pyridyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino- quinoline-3-carboxamide

5.23 8-(3,5-dichloro-2,4-difluoro- phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino- quinoline-3-carboxamide

5.24 N-indolin-1-yl-4-morpholino-8- (2,3,5-trifluorophenyl)quinoline-3-carboxamide

5.25 8-(4,6-dichloro-2-pyridyl)-N- (2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.26 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-8-(6-fluoropyrazin-2-yl)-4-morpholino-quinoline-3- carboxamide

5.27 8-[2-chloro-6- (trifluoromethyl)pyrimidin-4-yl]-N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-morpholino-quinoline-3-carboxamide

5.28 8-(6-chloro-5-fluoro-2-pyridyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.29 8-(6-chloro-3-fluoro-2-pyridyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.30 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-8-(6-ethoxypyrazin-2-yl)-4-morpholino-quinoline-3- carboxamide

5.31 4-(azetidin-1-yl)-N-(2,3-dihydro- 1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide

5.32 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-pyrrolidin-1-yl-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide

5.33 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4[2-methoxyethyl(methyl)amino]-8- (2,3,5-trifluorophenyl)quinoline-3-carboxamide

5.34 4-[bis(2-methoxyethyl)amino]-N- (2,3-dihydro-1,4-benzoxazin-4-yl)-8-(2,3,5- trifluorophenyl)quinoline-3- carboxamide

5.35 7-cyano-8-(3,5-dichlorophenyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.36 4-cyclopropyl-N-(2,3-dihydro- 1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide

5.37 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-(3-fluoroazetidin-1-yl)-8-(2,3,5-trifluorophenyl)quinoline- 3-carboxamide

5.38 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-(3-hydroxyazetidin-l-yl)-8-(2,3,5-trifluorophenyl)quinoline- 3-carboxamide

5.39 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-oxazolidin-3-yl-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide

5.40 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8- (2,3,5-trifluorophenyl)quinoline-3-carboxamide

5.41 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-7-fluoro-4-morpholino-8-(3,4,5-trifluorophenyl)quinoline- 3-carboxamide

5.42 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-isoxazolidin-2-yl-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide

5.43 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-morpholino-8-[1-(2,2,2-trifluoroethyl)pyrazol-4- yl]quinoline-3-carboxamide

5.44 8-(2,6-dichloropyrimidin-4-yl)-N- (2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.45 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-tetrahydropyran-4-yl-8-(2,3,5-trifluorophenyl)quinoline- 3-carboxamide

5.46 4-[acetyl(methyl)amino]-N-(2,3- dihydro-1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline- 3-carboxamide

5.47 8-(3,5-dichloro-2-fluoro-phenyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino- quinoline-3-carboxamide

5.48 8-(3,5-dichloro-2,4-difluoro- phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4- morpholino-quinoline-3- carboxamide

5.49 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-morpholino-8-(2,3,6-trifluoro-4-pyridyl)quinoline-3- carboxamide

5.50 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-8-(4-fluoro-2,6-dimethyl-phenyl)-4-morpholino-quinoline- 3-carboxamide

5.51 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-8-[4-ethylsulfanyl-6-(trifluoromethyl)pyrimidin-2-yl]- 4-morpholino-quinoline-3- carboxamide

5.52 8-[4-benzyloxy-6- (trifluoromethyl)pyrimidin-2-yl]-N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-morpholino-quinoline-3-carboxamide

5.53 [3-(2,3-dihydro-1,4-benzoxazin- 4-ylcarbamoyl)-8-(2,3,5-trifluorophenyl)-4- quinolyl]boronic acid

5.54 8-(3,5-dichloro-2,4-difluoro- phenyl)-7-fluoro-N-indolin-1-yl-4-morpholino-quinoline-3- carboxamide

5.55 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-(1-methoxyethyl)-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide

5.56 8-(3,5-dichloro-2,4-difluoro- phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4- (dimethylamino)-7-fluoro- quinoline-3-carboxamide

5.57 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-morpholino-8-(2,3,5,6-tetrafluorophenyl)quinoline-3- carboxamide

5.58 4-cyclopropyl-8-(3,5-dichloro- 2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7- fluoro-quinoline-3-carboxamide

5.59 8-[3,5- bis(trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin-4- yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide

5.60 8-(5-chloro-2,3-difluoro-phenyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino- quinoline-3-carboxamide

5.61 8-[3-chloro-5- (trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7- fluoro-4-morpholino-quinoline-3-carboxamide

5.62 8-(3,5-dichloro-2,4-difluoro- phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4- [methoxy(methyl)amino]quinoline-3-carboxamide

5.63 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-morpholino-8-[4-(trifluoromethyl)phenyl]quinoline- 3-carboxamide

5.64 8-[3,5-dichloro-4- (trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4- morpholino-quinoline-3- carboxamide

5.65 8-(3-chloro-2,5,6-trifluoro- phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4- morpholino-quinoline-3- carboxamide

5.66 8-(3-chloro-5-cyano-phenyl)-N- (2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.67 8-(3-cyano-2,5-difluoro-phenyl)- N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3- carboxamide

5.68 N-(2,3-dihydro-1,4-benzoxazin-4- yl)-4-(2,2,2-trifluoro-l-methyl-ethyl)-8-(2,3,5- trifluorophenyl)quinoline-3- carboxamide

Example 6.14-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxamide

To a suspension of ethyl 6-hydroxypyrimidine-4-carboxylate (5.03 g,28.74 mmol) in DMF (25 mL) under N2-atmosphere was added1,3-dichloro-5,5-dimethlyhydantoin (3.48 g, 17.3 mmol). The mixture wasstirred overnight at rt. The reaction was partitioned between water (200mL) and EtOAc (100 mL), then it was extracted with EtOAc (2×75 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give ethyl5-chloro-6-hydroxy-pyrimidine-4-carboxylate. LCMS (method A) R_(t)=0.54min, m/z=203.0 [M+H]⁺.

To a suspension of ethyl 5-chloro-6-hydroxy-pyrimidine-4-carboxylate(8.74 g, 28.1 mmol) in CH₃CN (100 mL) at rt under N2-atmosphere wasadded DIPEA (6.4 mL, 36 mmol) then phosphorous oxybromide (9.44 g, 31.28mmol) was added. The resulting mixture was stirred at rt. The reactionwas diluted with CH₂Cl₂ (100 mL) and slowly poured into water (100 mL).The mixture was then extracted with CH₂Cl₂ (3×100 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The oil was purified by column chromatography(0-10% EtOAc in cyclohexane) to give ethyl6-bromo-5-chloro-pyrimidine-4-carboxylate. LCMS (method A) R_(t)=0.98min, m/z=265.0 [M+H]⁺.

To a stirred solution of ethyl 6-bromo-5-chloro-pyrimidine-4-carboxylate(4.31 g, 14.9 mmol) and (3,5-dichlorophenyl) boronic acid (2.71 g, 14.20mmol) in 1,4-dioxane (55 mL) under N2-atmosphere was added K₂CO₃ (8.69g, 62.9 mmol) followed by tetrakis (triphenylphosphine) palladium (0)(732 mg, 0.63 mmol). The reaction was degassed and put underN2-atmosphere, then heated to 90° C. during 16 hours. The mixture wasdiluted with EtOAc (50 mL) and passed through Celite®. The combinedorganic filtrates were concentrated in vacuo. The residue was purifiedby column chromatography (0-20% EtOAc in cyclohexane) to give ethyl5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carboxylate. LCMS (method B)R_(t)=1.43 min, m/z=331.0 [M+H]⁺.

To a mixture of ethyl5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carboxylate (2.90 g, 8.75mmol) in THF (85 mL) and water (30 mL) at rt under N2-atmosphere wasadded lithium hydroxide (624 mg, 25.6 mmol). The resulting mixture washeated to 50° C. for 1 hour. The reaction was cooled to rt and thenconcentrated under reduced pressure to remove THF. The resultingsolution was diluted with water (50 mL) then acidified with 2M HCl untilthe pH=1, causing a solid to precipitate. The precipitate was filteredoff and washed with water (25 mL). The precipitate was then dried invacuo at 50° C. to give 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carboxylic acid. LCMS (method B) R_(t)=0.72 min, m/z=303.0[M+H]⁺.

A suspension of 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carboxylicacid (2.49 g, 7.82 mmol) in thionyl chloride (30 mL, 411 mmol) washeated to 80° C. under N2-atmosphere. DMF (0.5 mL, 6 mmol) was added andthe reaction fully dissolved. The reaction was then concentrated invacuo, taken up in toluene (20 mL) and azotroped (3 times) to give5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl chloride, which wasused without further purification.

To a solution of 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonylchloride (2.65 g, 7.82 mmol) in toluene (20 mL) at rt underN2-atmosphere was added NEt₃ (2 mL, 14 mmol) followed by ethyl3-(dimethylamino)prop-2-enoate (1.4 mL, 9.7 mmol). The reaction wasstirred at rt under N2-atmosphere. The reaction was diluted with EtOAc(125 mL) and filtered through Celite®. The Celite® was washed throughwith EtOAc (125 mL). The combined organic filtrates were concentrated invacuo. The residue was taken up in EtOAc (250 mL) and 2M HCl (aq, 100mL). The aq. layer was extracted with EtOAc (125 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give ethyl2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-(dimethylamino)prop-2-enoate.LCMS (method B) R_(t)=1.24 min, m/z=428.0 [M+H]⁺.

4-Methoxybenzylamine (1.20 mL, 9.09 mmol) was added to a solution ofethyl2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-(dimethylamino)prop-2-enoate (3.59 g, 6.29 mmol) in diethyl ether (25 mL) and EtOH (6mL) at rt under N2-atmosphere for 1 hour. The reaction was diluted withwater (150 mL) and extracted with CH₂Cl₂ (4×75 mL). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give ethyl2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-[(4-methoxyphenyl)methyl amino] prop-2-enoate. The material was taken on without anyfurther purification. LCMS (method B) R_(t)=1.49 min, m/z=520.0 [M+H]⁺.

To a solution of ethyl2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-[(4-methoxyphenyl)methylamino] prop-2-enoate (4.4 g, 5.66 mmol) in DMF (15 mL) at rt underN2-atmosphere was added K₂CO₃ (2.37 g, 17.1 mmol). The resulting mixturewas heated to 90° C. for 24 hours. The reaction was cooled to rt, thenpoured into water (300 mL) and extracted with CH₂Cl₂ (3×100 mL). Thecombined organic layers were washed with brine (200 mL) and dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography (0-5% MeOH in CH₂Cl₂) to give ethyl4-(3, 5-dichlorophenyl)-5-[(4-methoxyphenyl)methyl]-8-oxo-pyrido[3,2-d]pyrimidine-7-carboxylate. LCMS (method B) R_(t)=1.17 min, m/z=484.0[M+H]⁺.

To a solution of ethyl4-(3,5-dichlorophenyl)-5-[(4-methoxyphenyl)methyl]-8-oxo-pyrido[3,2-d]pyrimidine-7-carboxylate(1.89 g, 3.70 mmol) in CH₂Cl₂ (75 mL) and DMF (0.5 mL) at rt underN2-atmosphere was added slowly oxalyl chloride (2 mL, 23.1 mmol). Thereaction was heated to reflux at 60° C. for 1 hour. The mixture wascooled to rt, then quenched by the addition of sat. aq. NaHCO₃ solution(200 mL) and extracted with CH₂Cl₂ (3×100 mL). The combined organiclayers were combined and then concentrated in vacuo to give ethyl8-chloro-4-(3,5-dichlorophenyl)pyrido[3,2-d]pyrimidine-7-carboxylate.LCMS (method B) R_(t)=1.52 min, m/z=382.0 [M+H]⁺.

To a solution of ethyl8-chloro-4-(3,5-dichlorophenyl)pyrido[3,2-d]pyrimidine-7-carboxylate(502 mg, 0.93 mmol) in THF (10 mL, 123 mmol) at rt under N2-atmospherewas added dropwise morpholine (0.17 mL, 1.9 mmol). The reaction wasstirred at rt for 3 hours. The reaction was then quenched with sat. aq.NaHCO₃ solution (50 mL) and extracted with CH₂Cl₂ (3×25 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatography(10-25% EtOAc in cyclohexane) to give ethyl4-(3,5-dichlorophenyl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxylate.LCMS (method B) R_(t)=1.56 min, m/z=433.0 [M+H]⁺.

To a mixture of ethyl4-(3,5-dichlorophenyl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxylate(337.5 mg, 0.717 mmol) in 1,4-dioxane (15 mL) and water (5 mL) at rtunder N2-atmosphere was added lithium hydroxide (61.6 mg, 2.52 mmol).The resulting mixture was heated to 80° C. The reaction was concentratedin vacuo and the residue was taken up in water (20 mL) and acidifiedwith 2M HCl. The resulting precipitate was filtered off and washed withwater (20 mL), then dried in vacuo at 45° C. overnight to give4-(3,5-dichlorophenyl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxylicacid. LCMS (method B) R_(t)=0.80 min, m/z=405.0 [M+H]⁺.

To a suspension of4-(3,5-dichlorophenyl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxylicacid (125.1 mg, 0.31 mmol) in THF (3 mL) was added NEt₃ (0.18 mL, 1.3mmol), followed by PyBOP (259 mg, 0.49 mmol). The reaction was stirredat rt under N2-atmosphere. 2,3-Dihydro-1,4-benzoxazin-4-amine (60.5 mg,0.40 mmol) in THF (1 mL) was then added to the reaction. The mixture wasstirred for 22 hours at rt. The mixture was diluted with brine (25 mL)and extracted with CH₂Cl₂ (3×15 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography (5-40% EtOAc in cyclohexane) to givethe title compound. LCMS (method B) R_(t)=1.38 min, m/z=537.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) δ [ppm]: 10.75 (s, 1H), 9.38 (s, 1H), 8.92 (s,1H), 8.31 (d, J=2 Hz, 2H), 7.87 (t, J=2 Hz, 1H), 7.01 (dd, J=1.2, 8 Hz,1H), 6.85 (td, J=1.6, 8.4 Hz, 1H), 6.69-6.78 (m, 2H), 4.38 (t, J=4.4 Hz,2H), 3.86 (t, J=4 Hz, 4H), 3.63-3.73 (m, 6H).

Example 7.18-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,6-naphthyridine-3-carboxamide

To a stirred solution of 3,4-dihydro-2H-1,4-benzoxazine in EtOH (8 mL)was added sodium nitrite (612 mg, 8.87 mmol) in water (3.2 mL) dropwiseat 0° C. After 5 min, HCl (0.8 mL) was added dropwise and the reactionmixture left to stir at 0° C. for 2 hours. NaOH (2.96 g, 74 mmol) inwater (7.5 mL) was added to the reaction mixture dropwise, followed bysodium dithionate (4.4 g, 22.2 mmol) at 0° C. The resulting reactionmixture was heated to 90° C. for 4 hours. The reaction mixture wasdissolved in EtOAc (20 mL), washed with water (10 mL) and brine (10 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated invacuo. The crude compound was purified by column chromatography elutingwith 0-50% EtOAc in petroleum ether. LCMS (method C) R_(t)=0.89 min,m/z=152.36 [M+H]⁺.

A mixture of 3-bromopyridin-4-amine (10.0 g, 57.8 mmol) and diethyl2-(ethoxymethylene)propanedioate (32.8 mL, 173 mmol) was heated to 120°C. for 16 hours. The reaction mixture was allowed to rt, reduced todryness in vacuo and purified by column chromatography eluting with0-50% EtOAc in petroleum ether to afford diethyl2-[[(3-bromo-4-pyridyl)amino]methylene]propanedioate. LCMS (method C)R_(t) 1.71 min, m/z=343.19 [M+H]+.

A solution of 2-[[(3-bromo-4-pyridyl)amino]methylene]propanedioate (2.8g, 8.12 mmol) was in diphenyl ether (42 mL) was heated to 250° C. for 30min. The reaction mixture was allowed cool to rt and petroleum ether (50mL) was added. The resulting solid compound was filtered, washed withpetroleum ether (50 mL) and dried in vacuo to afford ethyl8-bromo-4-hydroxy-1,6-naphthyridine-3-carboxylate. LCMS (method C)R_(t)=1.16 min, m/z=297.11 [M+H]+.

Ethyl 8-bromo-4-hydroxy-1,6-naphthyridine-3-carboxylate (4.3 g, 14.5mmol) was added to POCl₃ (43 mL) and heated to 90° C. for 6 hours. Thereaction mixture was allowed to cool to rt, concentrated under reducedpressure. The residue was diluted in EtOAc (100 mL), washed with sat.aq. NaHCO₃ solution (3×30 mL) and brine (20 mL). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by column chromatography eluting with 0-20%EtOAc in petroleum ether. LCMS (method C) R_(t)=2.30 min, m/z=315.09[M+H]+.

To a stirred solution of ethyl8-bromo-4-chloro-1,6-naphthyridine-3-carboxylate (3 g, 9.5 mmol) in THF(60 mL) was added morpholine (4.1 g, 47.5 mmol) at rt and stirred for 30min. The reaction mixture was concentrated to dryness under reducedpressure. The crude product was purified by column chromatographyeluting with 0-50% EtOAc in petroleum ether to afford ethyl8-bromo-4-morpholino-1,6-naphthyridine-3-carboxylate. LCMS (method C)R_(t)=1.65 min, m/z=366.24 [M+H]+.

To a stirred solution of ethyl8-bromo-4-morpholino-1,6-naphthyridine-3-carboxylate (0.8 g, 2.18 mmol)and (3,5-dichlorophenyl)boronic acid (1.04 g, 5.46 mmol) in1,4-dioxane/water (16/4 mL) were added Cs₂CO₃ (2.13 g, 6.55 mmol)followed by tri-tert-butylphosphonium tetrafluoroborate (0.127 g, 0.43mmol) and degassed under N2 for 10 min. PdCl2(dppf) (0.16 g, 0.21 mmol)was added to reaction mixture and heated to 90° C. for 16 hours. Thereaction mixture was dissolved in EtOAc (30 mL), washed with water (15mL) and brine (10 mL). The organic layer was dried over anhydrous Na₂SO₄and concentrated to dryness. The crude product was purified by columnchromatography eluting with 0-50% EtOAc in petroleum ether. LCMS (methodC) R_(t)=2.33 min, m/z=432.30 [M+H]⁺.

To a stirred solution of ethyl8-(3,5-dichlorophenyl)-4-morpholino-1,6-naphthyridine-3-carboxylate(0.55 g, 1.27 mmol) in EtOH:THF:water (1:1:1, 9 mL) was added LiOH.H₂O(0.16 g, 3.81 mmol) at rt and heated to 70° C. for 4 hours. The reactionmixture was allowed to cool down to rt and then concentrated to removesolvents. pH was adjusted to 6-7 with aq. 0.5 M HCl solution undercooling condition (0° C.) and extracted with EtOAc (3×30 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated to dryness. LCMS (method C) R_(t)=2.15 min, m/z=403.9[M+H]⁺.

To a stirred solution of8-(3,5-dichlorophenyl)-4-morpholino-1,6-naphthyridine-3-carboxylic acid(0.3 g, 0.74 mmol) and 2,3-dihydro-1,4-benzoxazin-4-amine (134 mg, 0.89mmol) in DMF (5 mL) were added HATU (0.34 g, 0.89 mmol) and DIPEA (0.38g, 2.2 mmol) at rt. The resulting reaction mixture was heated to 60° C.for 16 hours. The reaction mixture was quenched by adding water (5 mL)and extracted with EtOAc (3×15 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by columnchromatography eluting with 0-100% EtOAc in petroleum ether to affordtitle compound. LCMS (method D) R_(t)=2.12 min, m/z=536.24 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) δ [ppm]: 10.75 (s, 1H), 9.03 (s, 1H), 8.84 (s,1H), 7.77 (d, J=2 Hz, 2H), 7.72 (t, J=2 Hz, 1H), 7.03 (m, 1H), 6.85 (td,J=2, 7.2 Hz, 1H), 6.72-6.78 (m, 2H), 4.38 (t, J=4.4 Hz, 2H), 3.92 (t,J=3.6 Hz, 4H), 3.69 (br s, 2H), 3.39 (t, J=4 Hz, 4H).

Example 8.1N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide

To a stirred solution of 8-bromo-1H-3,1-benzoxazine-2,4-dione (0.8 g,3.3 mmol) and ethyl 3-oxobutanoate (0.86 g, 6.61 mmol) in DMA (5 mL) wasadded NaOH (0.132 g, 3.3 mmol). The resulting reaction mixture wasstirred for 12 h at 100° C. The mixture was quenched by adding water(200 mL) and extracted with EtOAc (3×50 mL). The combined organic layerwas washed with brine (50 mL), dried over Na₂SO₄ and concentrated underreduced pressure. The crude compound was triturated with n-pentane (30mL) to afford ethyl 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylate.LCMS (method C) R_(t)=1.54 min, m/z=310.22 [M+H]⁺.

To a stirred solution of ethyl8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylate (0.3 g, 0.96 mmol) inEtOH (5 mL) was added KOH (0.814 g, 14.5 mmol) at rt and heated to 80°C. for 24 h. The reaction mixture was allowed to rt and concentrated.The pH of the residue was adjusted to 1-2 using aqueous 2 N HCl solutionand the precipitated solid was filtered, washed with water (10 mL) anddried to afford 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylic acid.LCMS (method C) R_(t)=1.46 min, m/z=280.05 [M−H]⁻.

A mixture of 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylic acid (0.2g, 0.7 mmol) and POCl₃ (10 mL) was heated to 90° C. for 2 h. Thereaction mixture was allowed to cool to rt, and concentrated underreduced pressure to afford8-bromo-4-chloro-2-methyl-quinoline-3-carbonyl chloride.

To a stirred solution of 2,3-dihydro-1,4-benzoxazin-4-amine (0.188 g,1.25 mmol) in THF (3 mL) was added DIPEA (0.342 g, 2.5 mmol) and cooledto 0-5° C. A solution of 8-bromo-4-chloro-2-methyl-quinoline-3-carbonylchloride (0.2 g, 0.62 mmol) in 2 mL THF was added to the reactionmixture and allowed to stir at rt. The reaction mixture was quenched byadding water (100 mL) and extracted with EtOAc (2×50 mL). The combinedorganic layer was washed with brine (50 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycolumn chromatography, to obtain8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-quinoline-3-carboxamide.LCMS (method C) Rt=2.12 min, m/z=432.06 [M+H]⁺.

To a stirred solution of8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-quinoline-3-carboxamide(0.25 g, 0.57 mmol) and morpholine (0.5 g, 5.77 mmol) in THF (5 mL) wasadded Et₃N (0.116 g, 1.15 mmol). The reaction mixture stirred at rt for16 h. The reaction mixture was quenched by adding water (100 mL) andextracted with EtOAc (2×50 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure.The crude compound triturated with diethyl ether (30 mL) to obtain8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholino-quinoline-3-carboxamide.LCMS (method C) Rt=2.25 min, m/z=483.49 [M+H]⁺.

To a stirred solution of8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholino-quinoline-3-carboxamide(0.3 g, 0.62 mmol) and (2,3,5-trifluorophenyl) boronic acid (0.656 g,3.72 mmol) in 1,4-Dioxane (12 mL):water (3 mL) was added Cs₂CO₃,reaction mixture was de-gassed with N2 gas for 10 min followed by theaddition of [(t-Bu)₃PH]BF₄ (0.036 g, 0.12 mmol) and PdCl2(dppf) (0.045g, 0.06 mmol), and heated to 90° C. for 16 h. The reaction mixture wasquenched by adding water (200 mL) and extracted with EtOAc (2×100 mL).The combined organic layer was washed with brine (50 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by column chromatography and eluted with 10% EtOAc in petroleumether to obtain Example 8.1. LCMS (method C) Rt=2.29 min, m/z=535.22[M+H]⁺. ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.57 (s, 1H), 8.31 (d, J=7.6Hz, 2H) 7.79 (d, J=6.4 Hz, 2H), 7.69 (t, J=8.4 Hz, 1H), 7.59-7.61 (m,1H), 7.20-7.21 (m, 1H), 6.99 (d, J=6.8 Hz, 1H), 6.85 (td, J=1.6, 6.8 Hz,1H), 6.74-6.79 (m, 2H), 4.39 (t, J=4 Hz, 2H), 3.87 (t, J=4 Hz, 4H), 3.72(br s, 2H), 3.32 (br s, 4H), 2.55 (s, 3H).

Example 8.2N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide

Step 1: To a stirred solution of 7-bromoindoline-2,3-dione (2.5 g, 11.06mmol) and ethyl 4,4,4-trifluorobut-2-ynoate (1.83 g, 11.06 mmol) in DMF(15 mL) was added Na₂CO₃ (2.34 g, 22.12 mmol) followed by tert-butylhydroperoxide (TBHP, 0.99 g, 11.06 mmol). The reaction mixture wasstirred for 2 h at rt. The reaction mixture was quenched by adding water(20 mL) and extracted with ethy (2×30 mL). The combined organic layerwas washed with brine (3×30 mL), dried over Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by columnchromatography, eluting with 0-50% EtOAc in petroleum ether to obtainethyl 8-bromo-4-hydroxy-2-(trifluoromethyl) quinoline-3-carboxylate.LCMS (method C) Rt=2.29 min, m/z=364.14 [M+H]⁺.

Step 2: To a stirred solution of ethyl8-bromo-4-hydroxy-2-(trifluoromethyl) quinoline-3-carboxylate (1.75 g,4.80 mmol) in EtOH (10 mL) was added KOH (5.39 g, 96.12 mmol) at rt andheated to 90° C. for 24 h. The reaction mixture was allowed to rt andconcentrated. The pH of the residue was adjusted to 1-2 using aqueous 2N HCl solution and the precipitated solid filtered, washed with water(10 mL), diethyl ether (20 mL) and dried to afford8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylic acid. LCMS(method C) Rt=1.79 min, m/z=335.99 [M+H]⁺.

Step 3: A mixture of8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylic acid (1 g,2.97 mmol) and POCl₃ (10 mL) was heated to 90° C. for 2 h. The reactionmixture was allowed to rt and concentrated under reduced pressure toafford 8-bromo-4-chloro-2-(trifluoromethyl)quinoline-3-carbonylchloride.

Step 4: To a stirred solution of 2,3-dihydro-1,4-benzoxazin-4-amine (0.8g, 5.36 mmol) in THF (5 mL) was added DIPEA and cooled to 0-5° C. Asolution of 8-bromo-4-chloro-2-(trifluoromethyl) quinoline-3-carbonylchloride (1 g, 2.68 mmol) in 4 mL THF was added to the reaction mixtureand allowed to stir at rt for 16 h. The reaction was quenched by addingwater (20 mL) and extracted with EtOAc (2×30 mL). The combined organiclayer was washed with brine (20 mL), dried over Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by columnchromatography eluting with 0-100% EtOAc in petroleum ether to obtain8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-(trifluoromethyl)quinoline-3-carboxamide.LCMS (method C) Rt=2.23 min, m/z=486.04 [M+H]⁺.

Step 5: To a stirred solution of8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-(trifluoromethyl)quinoline-3-carboxamide(0.844 g, 1.73 mmol) in THF (6 mL) was added morpholine (1.5 mL, 17.34mmol) at rt and stirred for 16 h. The reaction mixture was concentratedto dryness. The crude was purified by column chromatography eluting with0-50% EtOAc in petroleum ether to afford8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)quinoline-3-carboxamide.LCMS (method C) Rt=2.18 min, m/z=537.08 [M+H]⁺.

Step 6: To a stirred solution of8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)quinoline-3-carboxamideand (2,3,5-trifluorophenyl) boronic acid (0.687 g, 3.91 mmol) in1,4-dioxane (15 mL):water (5 mL) was added Cs₂CO₃ (0.636 g, 1.95 nmmol).The reaction mixture was de-gassed with N2 gas for 10 min followed bythe addition of [(t-Bu)₃PH]BF₄ (0.075 g, 0.26 mmol) and PdCl2(dppf)(0.095, 0.13 mmol). The reaction mixture was heated to 90° C. for 16 h.The reaction mixture was quenched by adding water (150 mL) and extractedwith EtOAc (3×50 mL). The combined organic layer was washed with brine(30 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude compound was purified by column chromatography eluting with 0-14%EtOAc in petroleum ether to afford Example 8.2 as a white solid. LCMS(method C) Rt=2.27 min, m/z=589.39 [M+H]⁺. 1H NMR (400 MHz, DMSO) δ[ppm]: 10.62 (s, 1H), 8.45 (d, J=8.4 Hz, 2H), 8.03 (d, J=7.2 Hz, 2H),7.94 (t, J=8.4 Hz, 1H), 7.65-7.67 (m, 1H), 7.29-7.31 (m, 1H), 7.03 (d,J=7.6 Hz, 1H), 6.83-6.87 (mz, 1H), 6.76-6.80 (m, 2H), 4.39 (t, J=3.6 Hz,2H), 3.87 (br s, 4H), 3.64 (br s, 2H), 3.43 (br s, 4H).

Experimental Details for Compounds in the Tables:

Ex. HPLC NMR 2.2 R_(t) = 1.43 ¹H NMR (400 MHz, DMSO-C) δ [ppm]: 10.6 (s,1 min, m/z = H), 8.88 (s, 1 H), 8.67 (d, J = 5.9 Hz, 1 H), 8.12- 4948.08 (m, 3 H), 7.75 (t, J = 2 Hz, 1 H), 7.09-7.03 (m, [M + H]⁺/ 1 H),6.99 (d, J = 6.4 Hz, 1 H), 6.93 (d, J = 7.9 Hz, Method B 1 H), 6.70-6.64(m, 1 H), 3.29 (m, 2 H), 3.13 (s, 6 H), 2.77 (t, J = 6.2 Hz, 2 H), 2.05(quint, J = 5.9 Hz, 2 H) 2.3 R_(t) = 1.32 ¹H NMR (400 MHz, DMSO-d6) δ[ppm]: 10.81 (s, min, m/z = 1 H), 9.01 (s, 1 H), 8.73 (d, J = 6 Hz, 1H), 8.11 (d, 534.0 J = 2 Hz, 2 H), 8.09 (d, J = 5.6 Hz, 1 H), 7.76 (t,[M − H]⁻/ J = 2 Hz, 1 H), 7.05 (dd, J = 1.2, 7.6 Hz, 1 H), 6.86 Method B(td, J = 1.6, 6.8 Hz, 1 H), 6.71-6.79 (m, 2 H), 4.39 (t, J = 4.4 Hz, 2H), 3.90 (t, J = 4 Hz, 4 H), 3.7 (br s, 2 H), 3.31 (br s, 4H) 2.4 R_(t)= 2.38 ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.9 (s, min, m/z = 1 H), 8.92(s, 1 H), 8.74 (d, J = 6 Hz, 1 H), 8.14 (d, 522.61 J = 5.6 Hz, 1 H),7.68-7.75 (m, 1 H), 7.34-7.37 (m, [M + H]⁺/ 1 H), 7.02 (dd, J = 1.2, 8Hz, 1 H), 6.72-6.85 (m, 3 Method C H), 4.38 (t, J = 4.4 Hz, 2 H), 3.90(t, J = 4 Hz, 4 H), 3.68 (br s, 2 H), 3.31 (br s, 4 H) 2.5 R_(t) = 2.35¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.9 (s, min, m/z = 1 H), 8.92 (s, 1H), 8.79 (d, J = 6 Hz, 1 H), 8.10 (d, 496.30 J = 5.6 Hz, 1 H), 7.69-7.76(m, 1 H), 7.34-7.39 (m, [M + H]⁺/ 1 H), 7.13 (dd, J = 1.6, 8 Hz, 1 H),6.82-6.86 (m, 1 Method D H), 6.74-6.76 (m, 2 H), 4.36 (t, J = 4 Hz, 2H), 3.60- 3.63 (m, 5 H), 3.36 (s, 3 H) 2.6 R_(t) = 2.71 ¹H NMR (400 MHz,DMSO-d6) δ [ppm]: 10.81 (s, min, m/z = 1 H), 9.01 (s, 1 H), 8.76 (d, J =5.6 Hz, 1 H), 8.48 570.35 (s, 1 H), 8.39 (s, 1 H), 8.12 (d, J = 6 Hz, 1H), 8.03 [M + H]⁺/ (s, 1 H), 7.05 (dd, J = 1.2, 8 Hz, 1 H), 6.84-6.89(m, Method D 1 H), 6.73-6.79 (m , 2 H), 4.39 (t, J = 4 Hz, 2 H), 3.90(t, J = 4 Hz, 4 H), 3.71 (br s, 2 H) 2.7 R_(t) = 2.92 ¹H NMR (400 MHz,DMSO-d6) δ [ppm]: 10.80 (s, min, m/z = 1 H), 8.87 (s, 1 H), 8.71 (d, J =5.6 Hz, 1 H), 8.11 536.0 (d, J = 6 Hz, 1 H), 7.77 (dd, J = 1.6, 8 Hz, 1H), [M + H]+/ 7.51 (t, J = 8 Hz, 1 H), 7.45 (dd, J = 1.6, 7.6 Hz, 1Method D H), 7.01 (dd, J = 0.8, 8 Hz, 1 H), 6.82 (td, J = 2, 8.8 Hz, 1H), 6.74-6.78 (m, 2 H), 4.37 (t, J = 4.4 Hz, 2 H), 3.90 (t, J = 4 Hz, 4H), 3.68 (br s, 2 h), 3.32 (br s, 4 H) 2.8 R_(t) = 2.68 ¹H NMR (400 MHz,DMSO-d6) δ [ppm]: 90° C.: min, m/z = 10.53 (s, 1 H), 8.95 (s, 1 H), 8.70(d, J = 5.6 Hz, 1 554.24 H), 8.35 (d, J = 6.4 Hz, 2 H), 8.07 (d, J = 5.6Hz, 1 [M + H]⁺/ H), 7.01 (d, J = 8 Hz, 1 H), 6.87 (td, J = 1.6, 8.4Method C Hz, 1 H), 6.70-6.78 (m, 2 H), 4.37 (t, J = 4.4 Hz, 2 H), 3.90(t, J = 4 Hz, 4 H), 3.71 (t, J = 4.4 Hz, 2H), 3.45 (t, J = 4.4 Hz, 4 H)2.9 R_(t) = 1.78 ¹H NMR (400 MHz, DMSO-d6) δ [ppm] 90° C.: min, m/z =10.55 (s, 1 H), 9.23 (d, J = 1.6 Hz, 1 H), 8.94 (s, 1 503.19 H), 8.74(d, J = 6 Hz, 1 H), 8.69 (d, J = 2.4 Hz, 1 [M + H]⁺/ H), 8.56 (t, J = 2Hz, 1 H), 7.95 (d, J = 5.6 Hz, 1 Method C H), 7.01 (dd, J = 0.8, 7.6 Hz,1 H), 6.85 (td, J = 1.6, 8.4 Hz, 1 H), 6.70-6.78 (m, 2 H), 4.37 (t, J =4.4 Hz, 2 H), 3.90 (t, J = 4.4 Hz, 4 H), 3.71 (t, J = 4.8 Hz, 2 H), 3.36(t, J = 4.8 Hz, 4 H) 2.10 R_(t) = 2.09 ¹H NMR (400 MHz, DMSO-d6) δ [ppm]90° C.: min, m/z = 10.55 (s, 1 H), 8.88 (s, 1 H), 8.73 (d, J = 5.6 Hz, 1503.19 H), 8.12 (d, J = 6 Hz, 1 H), 7.53-7.58 (m, 1 H), [M + H]⁺/7.23-7.28 (m, 1 H), 6.99-7.01 (m, 1 H), 6.83 (td, Method C J = 1.6, 8.8Hz, 1 H), 6.73-6.77 (m, 2 H), 4.37 (t, J = 4.4 Hz, 2 H), 3.70 (t, J =4.4 Hz, 2 H), 3.55-3.58 (m, 4 H), 2.91-2.99 (m, 4 H) 2.11 R_(t) = 1.83¹H NMR (400 MHz, DMSO-d6) δ [ppm] 90° C.: min, m/z = 10.6 (s, 1 H), 8.95(s, 1 H), 8.76 (d, J = 5.6 Hz, 1 503.19 H), 8.26 (d, J = 5.6 Hz, 1 H),7.55-7.58 (m, 1 H), [M + H]⁺/ 7.26-7.28 (m, 1 H), 6.99-7.01 (m, 1 H),6.99 (dd, Method C J = 0.8, 7.6 Hz, 1 H), 6.84 (td, J = 1.6, 8.4 Hz, 1H), 6.75-6.77 (m, 2 H), 4.38 (t, J = 4.4 Hz, 2 H), 3.68- 3.75 (m, 6 H),3.45-3.47 (m, 4 H) 2.12 R_(t) = 2.20 1H NMR (400 MHz, DMSO) δ [ppm] 90°C.: 10.53 min, m/z = (s, 1 H), 8.94 (s, 1 H), 8.70 (d, J = 5.6 Hz, 1 H),522.75 8.13 (m, 2 H), 8.07 (d, J = 6 Hz, 1 H), 7.01 (d, J = [M + H]+/6.8 Hz, 1 H), 6.85 (t, J = 6.8 Hz, 1 H), 6.70-6.78 Method C (m, 2 H),4.37 (t, J = 4.4 Hz, 2 H), 3.89 (t, J = 4.8 Hz, 4 H), 3.71 (t, J = 4.8Hz, 2 H), 3.35 (t, J = 4.4 Hz, 4 H). 3.2 R_(t) = 1.27 ¹H NMR (400 MHz,DMSO-d6) δ [ppm]: 10.57 (s, min, m/z = 1 H), 8.94 (d, J = 4 Hz, 1 H).8.62 (s, 1 H), 7.75 494.0 (dd, J = 1.6, 8 Hz, 1 H), 7.68 (d, J = 4 Hz, 1H), [M + H]⁺/ 7.49 (t, J = 7.6 Hz, 1 H), 7.38 (dd, J = 1.2, 7.6 Hz,Method B 1 H), 6.95 (dd, J = 1.6, 8 Hz, 1 H), 3.67-3.82 (m, 3 H), 4.36(t, J = 4.4 Hz, 2 H), 3.65 (br s, 2H), 3.32 (s, 6H) 3.3 R_(t) = 1.36 ¹HNMR (400 MHz, DMSO-d6) δ [ppm]: 10.64 (s, min, m/z = 1 H), 8.96 (d, J =4.4 Hz, 1 H), 8.81 (s, 1 H), 7.84 536.0 (d, J = 4.8 Hz, 1 H), 7.74-7.77(m, 3 H), 6.98 (dd, [M + H]⁺/ J = 1.2, 8 Hz, 1 H), 6.84 (td, J = 1.6,7.2 Hz, 1 H), Method B 6.69-6.78 (m, 2 H), 4.38 (t, J = 4.4 Hz, 2 H),(t, J = 4 Hz, 4 H), 3.69 (br s, 2 H), 3.64 (t, J = 4 Hz, 4 H) 3.4 Rt =2.06 ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.64 (s, min, m/z = 1 H), 9.01(d, J = 4.4 Hz, 1 H), 8.78 (s, 1 H), 7.83 522.29 (d, J = 4 Hz, 1 H),7.67-7.74 (m, 1 H), 7.31-7.33 (m, [M + H]+/ 1 H), 6.97 (d, J = 7.6 Hz, 1H), 6.82 (t, J = 7.2 Hz, Method C 1 H), 6.69-6.77 (m, 2 H), 4.37 (t, J =4 Hz, 2 H), 3.86 (br s, 74 H), 3.65-3.68 ( m, 6 H). 5.2 R_(t) = 1.29 ¹HNMR (400 MHz, DMSO-d6) δ [ppm]: 10.69 (s, min, 1 H), 8.77 (s, 1 H), 8.32(dd, J = 2.4, 7.2 Hz, 1 H), m/z = 7.70-7.75 (m, 3 H), 7.46 (t, J = 7.6Hz, 1 H), 7.36 535.5 (dd, J = 1.6, 7.6 Hz, 1 H), 7.00 (dd, J = 1.2, 8Hz, 1 [M + H]⁺/ H), 6.82 (td, J = 2, 7.2 Hz, 1 H), 6.69-6.77 (m, 2 H),Method B 4.38 (t, J = 4.4 Hz, 2 H), 3.89 (t, J = 4 Hz, 4 H), 3.68 (br s,2 H), 3.30 (t, J = 3.2 Hz, 4 H) 5.3 R_(t) = 1.41 ¹H NMR (400 MHz,DMSO-d6) δ [ppm]: 10.71 (s, min, m/z = 1 H), 8.88 (s, 1 H), 8.31 (dd, J= 0.8, 8.4 Hz, 1 H), 535.0 7.88 (dd, J = 1.2, 7.2 Hz, 1 H), 7.74 (t, J =7.2 Hz, 1 [M + H]⁺/ H), 7.03 (dd, J = 1.6, 8.4 Hz, 1 H), 6.85 (td, J =2, Method B 7.2 Hz, 1 H), 6.70-6.79 (m, 2 H), 4.39 (t, J = 4 Hz, 2 H),3.89 (t, J = 4 Hz, 4 H), 3.7 (br s, 2 H), 3.28 (t, J = 4 Hz, 2 H) 5.4R_(t) = 2.12 ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.70 (s, min, m/z = 1H), 8.85 (s, 1 H), 8.42 (m, 1 H), 7.66-7.75 (m, 2 539.31 H), 7.29-7.31(m, 1 H), 7.01 (dd, J = 1.2, 8.4 Hz, 1 [M + H]⁺/ H), 6.83 (td, J = 1.6,8.8 Hz, 1 H), 6.73-6.78 (m, 2 Method C H), 4.38 (t, J = 4.4 Hz, 2 H),3.88 (m, 4 H), 3.68 (br s, 2H), 3.29 (m, 4 H) 5.5 R_(t) = 3.07 ¹H NMR(400 MHz, DMSO-d6) δ [ppm]: 10.72 (s, min, m/z = 1 H), 8.87 (s, 1 H),8.78 (d, J = 2 Hz, 1 H), 8.67 (d, 502.44 J = 2 Hz, 1 H), 8.33-8.35 (m, 1H), 8.21 (t, J = 2 [M + H]⁺/ Hz, 1 H), 7.95 (dd, J = 0.8, 7.2 Hz, 1 H),7.46-7.78 Method D (m, 1 H), 7.03 (dd, J = 1.2, 8 Hz, 1 H), 6.85 (td, J= 1.6, 8.4 Hz, 1 H), 6.72-6.79 (m, 2 H), 4.39 (t, J = 4.4 Hz, 2 H), 3.89(m, 4 H), 3.71 (br s, 2 H), 3.30 (m, 4 H) 5.6 R_(t) = 1.78 ¹H NMR (400MHz, DMSO-d6) δ [ppm] 90° C.: min, m/z = 10.55 (s, 1 H), 9.23 (d, J =1.6 Hz, 1 H), 8.94 (s, 1 503.19 H), 8.74 (d, J = 6 Hz, 1 H), 8.69 (d, J= 2.4 Hz, 1 [M + H]⁺/ H), 8.56 (t, J = 2 Hz, 1 H), 7.95 (d, J = 5.6 Hz,1 Method C H), 7.01 (dd, J = 0.8, 7.6 Hz, 1 H), 6.85 (td, J = 1.6, 8.4Hz, 1 H), 6.70-6.78 (m, 2 H), 4.37 (t, J = 4.4 Hz, 2 H), 3.90 (t, J =4.4 Hz, 4 H), 3.71 (t, J = 4.8 Hz, 2 H), 3.36 (t, J = 4.8 Hz, 4 H) 5.7R_(t) = 2.09 ¹H NMR (400 MHz, DMSO-d6) δ [ppm] 90° C.: min, m/z = 10.55(s, 1 H), 8.88 (s, 1 H), 8.73 (d, J = 5.6 Hz, 1 503.19 H), 8.12 (d, J =6 Hz, 1 H), 7.53-7.58 (m, 1 H), [M + H]⁺/ 7.23-7.28 (m, 1 H), 6.99-7.01(m, 1 H), 6.83 (td, J = Method C 1.6, 8.8 Hz, 1 H), 6.73-6.77 (m, 2 H),4.37 (t, J = 4.4 Hz, 2 H), 3.70 (t, J = 4.4 Hz, 2 H), 3.55-3.58 (m, 4H), 2.91-2.99 (m, 4 H) 5.8 R_(t) = 2.08 ¹H NMR (400 MHz, DMSO-d6) δ[ppm] 90° C.: min, m/z = 10.42 (s, 1 H), 8.80 (s, 1 H), 8.34-8.39 (m, 1H), 521.33 7.62 (t, J = 8.8 Hz, 1 H), 7.16 (m, 3 H), 6.97 (d, J = [M +H]⁺/ 7.2 Hz, 1 H), 6.82 (t, J = 7.6 Hz, 1 H), 6.70-6.76 Method C (m, 2H), 4.36 (br s, 2 H), 3.88 (br s, 4 H), 3.69 (br s, 2H), 3.31 (br s, 4H) 5.9 R_(t) = 1.52 ¹H NMR (400 MHz, DMSO-d6) δ [ppm] 90° C.: min, m/z =10.6 (s, 1 H), 9.17 (s, 1 H), 9.06 (s, 2 H), 8.82 (s, 1 521.33 H), 8.36(dd, J = 1.6, 8.8 Hz, 1 H), 7.94 (dd, J = 0.8, [M + H]⁺/ 6.8 Hz, 1 H),7.74-7.78 (m, 1 H), 6.99 (dd, J = 1.2, Method C 9.2 Hz, 1 H), 6.83 (td,J = 1.6, 8.4 Hz, 1 H), 6.75- 6.77 (m, 2 H), 4.37 (t, J = 4.4 Hz, 2 H),3.89 (t, J = 4.4 Hz, 4 H), 3.71 (t, J = 4.4 Hz, 2 H), 3.33 (t, J = 4.4Hz, 4 H) 5.10 R_(t) = 2.24 ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.71 (s,min, m/z = 1 H), 8.85 (dd, J = 1.2, 8.4 Hz, 1 H), 7.75-7.87 (m, 537.33 2H), 7.60-7.64 (m, 1 H), 7.22-7.25 (m, 1 H), 7.02 [M + H]⁺/ (dd, J = 1.2,6.8 Hz, 1 H), 6.70-6.78 (m, 3 H), 4.39 Method C (t, J = 4.4 Hz, 2 H),3.69 (br s, 2 H), 3.49 (br s, 4 H), 2.92 (br s, 2 H) 5.11 R_(t) = 3.16¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.75 (s, min, m/z = 1 H), 8.90 (s, 1H), 8.39 (dd, J = 1.2, 8.4 Hz, 1 H), 521.33 8.23 (s, 1 H), 8.16 (s, 1H), 8.06 (dd, J = 1.2, 7.2 [M + H]⁺/ Hz, 1 H), 7.79 (t, J = 7.2 Hz, 1H), 7.03 (dd, J = Method D 1.6, 8 Hz, 1 H), 6.85 (td, J = 1.6, 7.2 Hz, 1H), 6.74-6.79 (m, 2 H), 4.39 (t, J = 4.4 Hz, 2 H), 3.90 (t, J = 3.6 Hz,4 H), 3.71 (br s, 2 H), 3.31 (br s, 4 H) 5.12 R_(t) = 2.54 ¹H NMR (400MHz, DMSO-d6) δ [ppm]: 10.75 (s, min, m/z = 1 H), 8.90 (s, 1 H), 8.37(dd, J = 1.2, 8.4 Hz, 1 H), 536.09 7.99 (dd, J = 1.6, 7.2 Hz, 1 H), 7.86(s, 2 H), 7.77 [M + H]⁺/ (t, J = 7.2 Hz, 1 H), 7.03 (dd, J = 1.6, 8 Hz,1 H), Method C 6.86 (td, J = 1.6, 6.8 Hz, 1 H), 6.72-6.79 (m, 2 H), 4.39(t, J = 4.4 Hz, 2 H), 3.89 (t, J = 4 Hz, 4 H), 3.71 (br s, 2 H), 3.28(br s, 4 H) 5.13 R_(t) = 2.28 ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.71(s, min, m/z = 1 H), 8.83 (s, 1 H), 8.35 (dd, J = 1.2, 8.4 Hz, 1 H),553.38 7.85-7.89 (m, 2 H), 7.75 (t, J = 7.2 Hz, 1 H), 7.55 [M + H]⁺/ (m,1H), 7.02 (dd, J = 1.2, 8 Hz 1H), 6.84( td, J = Method C 1.6, 7.2 Hz, 1H), 6.74-6.78 (m, 2 H), 4.39 (t, J = 4.4 Hz, 2 H), 3.89 (t, J = 4 Hz, 4H), 3.70 (br s, 2 H), 3.28 (br s, 4 H) 5.14 R_(t) = 2.07 ¹H NMR (400MHz, DMSO-d6) δ [ppm]: 10.72 (s, min, m/z = 1 H), 8.82 (s, 1 H), 8.40(m, 1 H), 8.36 (dd, J = 1.2, 518.35 8.4 Hz, 1 H), 8.23 (dd, J = 2.8, 8Hz, 1 H), 7.91 (dd, [M + H]⁺/ J = 1.2, 7.2 Hz, 1 H), 7.76 (t, J = 7.2Hz, 1 H), 7.01 Method D (dd, J = 1.6, 8 Hz, 1 H), 6.84 (td, J = 1.6, 7.2Hz, 1 H), 6.73-6.78 (m, 2 H), 4.38 (t, J = 4.4 Hz, 2 H), 3.89 (t, J = 4Hz, 4 H), 3.69 (br s, 2 H), 3.25 (br s, 4 H) 5.15 Rt = 2.10 ¹H NMR (400MHz, DMSO-d6) δ [ppm]: 10.78 (s, min, m/z = 1 H), 10.78 (s, 1 H), 8.48(d, J = 8.4 Hz, 1 H), 7.89 569.30 (d, J = 6.8 Hz, 1 H), 7.78 (t, J = 8Hz, 1 H), 7.62- [M + H]+/ 7.64 (m, 1 H), 7.23-7.26 (m, 1 H), 7.02 (d, J= 8 Hz, Method C 1 H), 6.85 (td, J = 1.6 , 8Hz, 1 H), 6.70-6.79 (m, 2H),4.40 (t, J = 4 Hz, 2 H), 3.65-3.67 (m, 6 H), 3.50 (br s, 2 H) 5.16 Rt =2.11 ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.70 (s, min, m/z = 1 H), 8.80(s, 1 H), 8.33 (dd, J = 0.8, 8.4 Hz, 1 H), 521.41 7.68-7.82 (m, 2 H),7.59-7.66 (m, 2 H), 7.01 (dd, [M + H]+/ J = 0.8, 8 Hz, 1 H), 6.84 (td, J= 1.6, 8.4 Hz, 1 H), Method C 6.73-6.78 (m, 2 H), 4.38 (t, J = 4.4 Hz, 2H), 3.65- 3.67 (t, J = 3.6 Hz, 4 H), 3.39 (br s, 2 H), 3.28-3.30 (m, 4H) 5.17 Rt = 1.91 ¹H NMR (400 MHz, DMSO-d6) δ at 90° C.: 10.45 min, m/z= (s, 1 H), 9.34 (s, 1 H), 8.86 (s, 1 H), 8.72 (s, 1 H), 503.26 8.42 (d,J = 7.6 Hz, 1 H), 8.19 (d, J = 6.8 Hz, 1 H), [M + H]+/ 7.79 (t, J = 8Hz, 1 H) 7.00 (d, J = 7.6 Hz, 1 H), Method C 6.84 (t, J = 6.8 Hz, 1 H),6.71-6.77 (m, 2 H), 4.37 (t, J = 4.4 Hz, 2 H), 3.89 (t, J = 4 Hz, 4 H),3.72 (t, J = 4.4 Hz, 2 H), 3.34 (t, J = 4.4 Hz, 4 H) 5.18 Rt = 2.02 ¹HNMR (400 MHz, DMSO-d6) δ at 90° C. [ppm]: min, m/z = 10.41 (s, 1 H),8.78 (s, 1 H), 8.73 (s, 1 H), 8.47 (s, 1 536.20 H), 8.37 (d, J = 7.2 Hz,1 H), 7.72-7.80 (m, 2 H), [M + H]+/ 6.97 (d, J = 8 Hz, 1 H), 6.81 (t, J= 6.8 Hz, 1 H), Method C 6.67-6.75 (m, 2 H), 4.36 (t, J = 4.4 Hz, 2 H),3.89 (t, J = 4.4 Hz, 4 H), 3.69 (t, J = 4.4 Hz, 2 H), 3.34 (t, J = 4.4Hz, 4H) 5.19 Rt = 2.29 ¹H NMR (400 MHz, DMSO-d6) δ [ppm] at 90° C.: min,m/z = 10.42 (s, 1 H), 8.77 (s, 1 H), 8.36 (d, J = 8.4 Hz, 1 535.27 H),7.81 (d, J = 6.8 Hz, 1 H), 7.72 (t, J = 8 Hz, 1 [M + H]+/ H), 7.62-7.67(m, 1 H), 7.32-7.34 (m, 1 H), 6.98 (d, Method C J = 8 Hz, 1 H), 6.82 (t,J = 6.8 Hz, 1 H), 6.70-6.76 (m, 2 H), 4.37 (t, J = 4 Hz, 2 H), 3.89 (t,J = 4 Hz, 4 H), 3.70 (t, J = 4.4 Hz, 2 H), 3.34 (t, J = 4.4 Hz, 4 H)5.20 Rt = 2.18 ¹H NMR (400 MHz, DMSO-d6) δ [ppm] at 90° C.: min, m/z =10.42 (s, 1 H), 8.77 (s, 1 H), 8.36 (dd, J = 0.8, 8.4 539.48 Hz, 1 H),7.80 (d, J = 4.8 Hz, 1 H), 7.73 (t, J = 8.4 [M + H]+/ Hz, 1 H),7.40-7.47 (m, 1 H), 6.98 (d, J = 7.6 Hz, 1 Method C H), 6.82 (t, J = 6.8Hz, 1 H), 6.68-6.76 (m, 2 H), 4.36 (t, J = 4.4 Hz, 2 H), 3.89 (t, J =4.4 Hz, 4 H), 3.70 (t, J = 4.4 Hz, 2 H), 3.33 (t, J = 4.8 Hz, 4 H) 5.21Rt = 1.90 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z = 10.42 (s,1 H), 8.72 (d, J = 8.8 Hz, 1 H), 8.42 (s, 1 520.27 H), 8.38 (d, J = 8Hz, 1 H), 7.73-7.81 (m, 2 H), 6.97 [M + H]+/ (d, J = 7.6 Hz, 1 H), 6.81(t, J = 7.2 Hz, 1 H), 6.67- Method C 6.79 (m, 2 H), 4.36 (t, J = 4 Hz, 2H), 3.89 (t, J = 4 Hz, 4 H), 3.69 (t, J = 4.4 Hz, 2 H), 3.34 (t, J = 4.4Hz, 4 H). 5.22 Rt = 2.27 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min,m/z = 10.42 (s, 1 H), 8.87 (s, 1 H), 8.54 (s, 1 H), 8.42 (dd, 570.27 J =1.2, 8.4 Hz, 1 H), 8.20 (d, J = 6.8 Hz, 1 H), 8.01 [M + H]+/ (s, 1 H),7.78 (d, J = 7.2 Hz, 1 H), 7.01 (d, J = 7.6 Method C Hz, 1 H), 6.84 (t,J = 7.2 Hz, 1 H), 6.69-6.77 (m, 2 H), 4.38 (t, J = 4.4 Hz, 2 H), 3.90(t, J = 4.4 Hz, 4 H), 3.72 (t, J = 4.4 Hz, 2 H), 3.34 (t, J = 4.4 Hz, 4H). 5.23 Rt = 2.33 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z =10.43 (s, 1 H), 8.77 (s, 1 H), 8.36 (d, J = 8.4 Hz, 1 571.19 H), 7.82(d, J = 6.8 Hz, 1 H), 7.67-7.75 (m, 2 H), [M + H]+/ 6.98 (d, J = 8 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1 H), Method C 6.68-6.77 (m, 2 H), 4.37 (t, J =4 Hz, 2 H), 3.89 (t, J = 4 Hz, 4 H), 3.71 (t, J = 4 Hz, 2 H), 3.33 (brs, 4 H). 5.24 Rt = 2.16 ¹H NMR (400 MHz, DMSO) δ [ppm]: 8.80 (s, 1 H),min, m/z = 8.34 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 6.8 Hz, 1 H), 505.327.71-7.79 (m, 1 H), 7.61-7.65 (m, 1 H), 7.07-7.25 [M + H]+/ (m, 3 H),6.78-6.88 (m, 2 H), 3.90 (br, s, 4 H), 3.69 Method C (t, J = 8 Hz, 2 H),3.30 (br s, 4 H), 3.02 (t, J = 8 Hz, 2 H). 5.25 Rt = 2.12 ¹H NMR (400MHz, DMSO) δ [ppm] at 90° C.: min, m/z = 10.6 (br s, 1 H), 8.87 (s, 1H), 8.39 (dd, J = 1.2, 8.4 536.24 Hz, 1 H), 8.28 (d, J = 1.2 Hz, 1 H),8.18 (d, J = 6.4 [M + H]+/ Hz, 1 H), 7.75 (t, J = 8 Hz, 1 H), 7.69 (d, J= 1.2 Method C Hz, 1 H), 7.01 (d, J = 7.2 Hz, 1 H), 6.84 (t, J = 7.2 Hz,1 H), 6.68-6.77 (m, 2 H), 4.37 (t, J = 4.4 Hz, 2 H), 3.89 (t, J = 4.4Hz, 4 H), 3.71 (t, J = 4.4 Hz, 2 H), 3.33 (t, J = 4.4 Hz, 4 H). 5.26 Rt= 3.30 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z = 10.47 (br s,1 H), 9.38 (d, J = 4.8 Hz, 1 H), 8.87 (s, 487.45 1 H), 8.62 (d, J = 8.4Hz, 1 H), 8.41 (d, J = 8.4 Hz, [M + H]+/ 1 H), 8.19 (d, J = 6.8 Hz, 1H), 7.79 (t, J = 7.6 Hz, Method D 1 H), 7.00 (d, J = 7.6 Hz, 1 H), 6.84(t, J = 7.6 Hz, 1 H), 6.69-6.77 (m, 2 H), 4.38 (t, J = 4 Hz, 2 H), 3.89(t, J = 4 Hz, 4 H), 3.72 (t, J = 4 Hz, 2 H), 3.34 (t, J = 4.4 Hz, 4 H).5.27 Rt = 2.31 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z =10.46 (s, 1 H), 8.90 (d, J = 2.8 Hz, 1 H), 8.50 (d, 571.23 J = 8.4 Hz, 1H), 8.41 (d, J = 6.8 Hz, 1 H), 7.83 (t, [M + H]+/ J = 8 Hz, 1 H), 7.00(d, J = 8 Hz, 1 H), 6.84 (t, J = Method C 6.8 Hz, 1 H), 6.69-6.77 (m, 2H), 4.37 (t, J = 4.4 Hz, 2 H), 3.89 (q, J = 4.4 Hz, 4 H), 3.72 (t, J = 4Hz, 2 H), 3.34 (t, J = 4.4 Hz, 4 H). 5.28 Rt = 1.88 ¹H NMR (400 MHz,DMSO) δ [ppm] at 90° C.: min, m/z = 10.46 (br s, 1 H), 8.82 (s, 1 H),8.36 (dd, J = 1.2, 520.27 8.4 Hz, 1H), 8.21 (dd, J = 3.6, 8.4 Hz, 1H),8.10 [M + H]+/ (d, J = 6.8 Hz, 1 H), 7.95 (t, J = 8.4 Hz, 1 H), 7.73Method C (t, J = 7.6 Hz, 1 H), 7.00 (d, J = 7.6 Hz, 1 H), 6.82 (t, J =6.8 Hz, 1 H), 6.67-6.76 (m, 2 H), 4.37 (t, J = 4.4 Hz, 2 H), 3.88 (t, J= 4.4 Hz, 4 H), 3.71 (t, J = 4.4 Hz, 2 H), 3.34 (t, J = 4.4 Hz, 4 H).5.29 Rt = 1.92 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z =10.42 (s, 1 H), 8.73 (s, 1 H), 8.39 (dd, J = 1.6, 8.4 520.23 Hz, 1 H),7.82-7.87 (m, 2 H), 7.75 (t, J = Hz, 1 H), [M + H]+/ 7.60 (dd, J = 3.2,8.8 Hz, 1 H), 6.98 (d, J = 8.8 Hz, Method C 1 H), 6.82 (t, J = 6.8 Hz, 1H), 6.68-6.76 (m, 2 H), 4.36 (t, J = 4.4 Hz, 2 H), 3.89 (t, J = 4.4 Hz,4 H), 3.70 (t, J = 4.4 Hz, 2 H), 3.34 (t, J = 4.4 Hz, 4 H). 5.30 Rt =1.78 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.7 (s, 1 H), min, m/z = 8.91 (d,J = 9.6 Hz, 12 H), 8.36 (dd, J = 1.2, 8.4 Hz, 513.39 1 H), 8.29 (s, 1H), 8.23 (dd, J = 1.2, 7.2 Hz, 1 H), [M + H]+/ 7.80 (t, J = 8.4 Hz, 1H), 7.03 (dd, J = 1.2, 8 Hz, 1 Method C H), 6.86 (td, J = 1.6, 8.4 Hz, 1H), 6.71-7.79 (m, 2 H), 4.45 (q, J = 6.8 Hz, 2 H), 4.39 (t, J = 4.4 Hz,2 H), 3.89 (t, J = 3.6 Hz, 4 H), 3.71 (br s, 2 H), 3.32 (br s, 4 H),1.40 (t, J = 6.8 Hz, 3 H). 5.31 Rt = 1.64 ¹H NMR (400 MHz, DMSO) δ[ppm]:10.46 (s, 1 min, m/z = H), 8.56 (s, 1 H), 8.15 (d, J = 8.4 Hz, 1H), 7.70 (d, 491.75 J = 6.0 Hz, 1 H), 7.54-7.62 (m, 1 H), 7.5 (dd, J =[M + H]+/ 7.2, 8.8 Hz, 1 H), 7.15-7.21 (m, 1 H), 6.91 (dd, J = Method C1.6, 8.0 Hz, 1 H), 6.72-6.82 (m, 2 H), 6.66-6.69 (m, 1 H), 4.42-4.50 (m,4 H), 4.31-4.38 (m, 2 H), 3.61- 3.65 (m, 2 H), 2.37-2.45 (m, 2 H). 5.32Rt = 2.17 ¹H NMR (400 MHz, DMSO) δ [ppm]:10.52 (s, 1 min, m/z = H), 8.53(s, 1 H), 8.38 (d, J = 8.8 Hz, 1 H), 7.71 (d, 508.39 J = 6.8 Hz, 1 H),7.48-7.61 (m, 2 H), 7.18-7.22 (m, [M + H]+/ 1 H), 6.92 (d, J = 7.6 Hz, 1H), 6.81 (t, J = 6.8 Hz, Method C 1 H), 6.74 (d, J = 7.2 Hz, 1 H),6.64-6.72 (m, 1 H), 4.33-4.37 (m, 2 H), 3.62-3.74 (m, 6 H), 1.93-1.97(m, 4 H). 5.33 Rt = 2.22 ¹H NMR (400 MHz, DMSO) δ [ppm]:10.64 (s, 1 min,m/z = H), 8.81 (s, 1 H), 8.40 (dd, J = 1,2, 8.4 Hz, 1 H), 523.80 7.82(dd, J = 1.2, 7.8 Hz, 1 H), 7.58-7.75 (m, 2 H), [M + H]+/ 7.20-7.28 (m,1 H), 6.99 (dd, J = 8.0, 1.2 Hz, 1 H), Method C 6.80-6.85 (m, 1 H),6.75-6.78 (m, 1 H), 6.67-6.73 (m, 1 H), 4.35-4.39 (m, 2 H), 3.60-3.69(m, 4 H), 3.46 (t, J = 5.6 Hz, 2 H), 3.26 (s, 3 H), 3.09 (s, 3 H). 5.34Rt = 2.40 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z = 10.34 (s,1 H), 8.81 (s, 1 H), 8.37 (d, J = 8.4 Hz, 1 567.87 H), 7.79 (d, J = 6.8Hz, 1 H), 7.71 (t, J = 8.4 Hz, 1 [M + H]+/ H), 7.42-7.49 (m, 1 H),7.15-7.17 (m, 1 H), 6.93 (d, Method C J = 7.2 Hz, 1 H), 6.80 (t, J = 7.2Hz, 1 H), 6.75 (d, J = 6.4 Hz, 1 H), 6.67-6.71 (m, 1 H), 4.37 (t, J = 4Hz, 2 H), 3.68 (t, J = 4.4 Hz, 2 H), 3.53-3.67 (m, 8 H), 3.16 (s, 6 H).5.35 Rt = 2.33 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z =10.49 (s, 1 H), 8.87 (s, 1 H), 8.42 (d, J = 8.8 Hz, 1 560.38 H), 7.96(d, J = 8.8 Hz, 1 H), 7.69 (t, J = 1.6 Hz, 1 [M + H]+/ H), 7.55 (d, J =2 Hz, 2 H), 6.98 (d, J = 6.8 Hz, 1 Method C H), 6.81 (td, J = 1.2, 8 Hz,1 H), 6.69-6.75 (m, 2 H), 4.36 (t, J = 4.4 Hz, 2 H), 3.89 (t, J = 4.4Hz, 4 H), 3.69 (t, J = 4.4 Hz, 2 H), 3.33 (t, J = 4.8 Hz, 4 H). 5.36 Rt= 2.33 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z = 10.27 (s, 1H), 8.82 (s, 1 H), 8.69 (dd, J = 1.2, 8 Hz, 476.29 1 H), 7.78-7.86 (m, 2H), 7.44-7.50 (m, 1 H), 7.15- [M + H]+/ 7.17 (m,1 H), 6.96 (d, J = 7.2Hz, 1 H), 6.81 (td, J = Method C 1.2, 8 Hz, 1 H), 6.71-6.75 (m, 2 H),4.37 (t, J = 4.4 Hz, 2 H), 3.72 (t, J = 4.4 Hz, 2 H), 2.47-2.49 (m, 1H), 1.25-1.30 (m, 2 H), 0.80 (q, J = 5.6 Hz, 2H). 5.37 Rt = 1.69 ¹H NMR(400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z = 10.28 (s, 1 H), 8.57 (s, 1H), 8.13 (d, J = 8.4 Hz, 1 509.95 H), 7.70 (d, J = 6.8 Hz, 1 H), 7.52(t, J = 8 Hz, 1 [M + H]+/ H), 7.39-7.46 (m, 1 H), 7.01-7.12 (m, 1 H),6.90 Method C (d, J = 7.6 Hz, 1 H), 6.78 (t, J = 7.6 Hz, 1 H), 6.64-6.74 (m, 3 H), 5.41-5.56 (m, 1 H), 4.56-4.62 (m, 2 H), 4.33 (s, 2 H),3.65 (s, 1 H). 5.38 Rt = 2.03 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.:min, m/z = 10.20 (s, 1 H), 8.52 (s, 1 H), 8.13 (d, J = 8.4 Hz, 1 507.45H), 7.66 (d, J = 6.8 Hz, 1 H), 7.38-7.50 (m, 2 H), [M + H]+/ 7.09-7.11(m, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 6.78 Method C (t, J = 6.8 Hz, 1 H),6.64-6.73 (m, 2 H), 5.54 (d, J = 5.6 Hz, 1 H), 4.64-4.68 (m, 2 H),4.57-4.60 (m, 1 H), 4.33 (br s, 2 H), 4.21-4.24 (m, 2 H), 3.64 (br s, 2H). 5.39 Rt = 2.06 min, m/z = 507.35 [M + H]+/ Method C 5.40 Rt = 1.61¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z 10.18 (s, 1 H), 8.53(s, 1 H), 8.14 (d, J = 8.8 Hz, 1 533.76 H), 7.69 (t, J = 7.2 Hz, 1 H),7.50 (t, J = 8.4 Hz, 1 [M + H]+/ H), 7.41-7.43 (m, 1 H), 7.09 (m, 1 H),6.91 (d, J = Method C 8 Hz, 1 H), 6.80 (t, J = 7.2 Hz, 1 H), 6.73 (d, J= 8 Hz, 2 H), 6.67 (t, J = 7.2 Hz, 1 H), 4.73 (s, 4 H), 4.63 (s, 4 H),4.35 (br s, 2 H), 3.69 (br s, 2 H). 5.41 Rt = 2.28 ¹H NMR (400 MHz,DMSO) δ [ppm] at 90° C.: min, m/z = 10.43 (br s, 1 H), 8.80 (s, 1 H),8.35-8.39 (m, 1 H), 539.81 7.62 (d, J = 9.6 Hz, 1 H), 7.39 (t, J = 7.6Hz, 2 H), [M + H]+/ 6.98 (d, J = 7.6 Hz, 1 H), 6.82 (t, J = 7.2 Hz, 1H), Method C 6.67-6.76 (m, 2 H), 4.36 (t, J = 4 Hz, 2 H), 3.88 (t, J = 4Hz, 2 H), 3.69 (t, J = 4.4 Hz, 2 H), 3.31 (t, J = 4.4 Hz, 4 H). 5.42 Rt= 1.82 ¹H NMR (400 MHz, DMSO) d [ppm]: 10.18 (br s, 1 min, m/z = H),8.59 (s, 1 H), 8.25 (dd, J = 1.2, 8.4 Hz, 1 H), 507.42 7.58-7.83 (m, 3H), 7.07-7.24 (m, 1 H), 6.82 (t, J = [M + H]+/ 7.2 Hz, 1 H), 7.05 (d, J= 7.2 Hz, 1 H), 6.81 (td, J = Method C 1.2, 8.4 Hz, 2 H), 6.60-6.74 (m,2 H), 4.35 (t, J = 4 Hz, 2 H), 4.02 (t, J = 6.8 Hz, 2 H), 3.92 (t, J =6.8 Hz, 2 H), 3.63 (br s, 2 H), 2.29 (quint, J = 6.8 Hz, 2 H). 5.43 Rt =1.89 ¹H NMR (400 MHz, DMSO) d [ppm] at 90° C.: min, m/z = 10.44 (s, 1H), 8.86 (s, 1 H), 8.72 (s, 1 H), 8.28 (s, 1 539.81 H), 8.15 (dd, J =1.2, 8.8 Hz, 1 H), 8.05 (d, J = 6.8 [M + H]+/ Hz, 1 H), 7.39 (t, J = 8Hz, 2 H), 7.00 (d, J = 7.6 Method C Hz, 1 H), 6.85 (t, J = 6.8 Hz, 1 H),6.70-6.78 (m, 2 H), 5.15 (q, J = 9.2 Hz, 2 H), 4.38 (t, J = 4.4 Hz, 2H), 3.87 (t, J = 4.4 Hz, 4 H), 3.69 (t, J = 4.4 Hz, 2 H), 3.31 (t, J =4.4 Hz, 4 H). 5.44 Rt = 2.20 ¹H NMR (400 MHz, DMSO) d [ppm] at 90° C.:min, m/z = 10.50 (s, 1 H), 8.91 (s, 1 H), 8.58 (s, 1 H), 8.47 (d, 537.36J = 8.4 Hz, 1 H), 8.36 (d, J = 7.2 Hz, 1 H), 7.80 (t, [M + H]+/ J = 8Hz, 1 H), 7.01 (d, J = 8 Hz, 2 H), 6.84 (t, J = Method C 6.8 Hz, 1 H),6.69-6.77 (m, 2 H), 4.38 (t, J = 4.4 Hz, 2 H), 3.88 (t, J = 4.4 Hz, 4H), 3.72 (t, J = 4.4 Hz, 2 H), 3.32 (t, J = 4.4 Hz, 4 H). 5.45 Rt = 2.25¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z = 10.45 (s, 1 H),8.83 (s, 1 H), 8.59(d, J = 7.6 Hz, 1 520.36 H), 7.76-7.86 (m, 2 H),7.40-7.51 (m, 1 H), 7.13- [M + H]+/ 7.18 (m, 1 H), 6.99 (dd, J = 0.8, 8Hz, 2 H), 6.84 Method C (td, J = 1.6, 8.4 Hz, 1 H), 6.69-6.77 (m, 2 H),4.37 (t, J = 4.4 Hz, 2 H), 4.04-4.08 (m, 2 H), 3.74-3.83 (m, 1 H), 3.70(t, J = 4.4 Hz, 2 H), 3.56 (t, J = 10 Hz, 2 H), 2.44-2.54 (m, 2 H), 1.79(d, J = 11.2 Hz, 2 H). 5.46 Rt = 2.09 ¹H NMR (400 MHz, DMSO) δ [ppm] at90° C.: min, m/z = 10.47 (br s, 1 H), 9.16 (s, 1 H), 7.81-8.13 (m, 3 H),507.29 7.45-7.55 (m, 1 H), 7.15-7.25 (m, 1 H), 6.92 (d, J = [M + H]+/7.2 Hz, 1 H), 6.99-6.81 (m, 3 H), 4.37 (br s, 2 H), Method C 3.62 (br s,2 H), 3.42 (s, 1 H), 3.27 (s, 2 H), 2.29 (s, 1 H), 1.72 (s, 2 H). 5.47Rt = 2.47 ¹H NMR (400 MHz, DMSO) δ [ppm] at 90° C.: min, m/z = 10.45 (s,1 H), 8.83 (s, 1 H), 8.59(d, J = 7.6 Hz, 1 571.19 H), 7.76-7.86 (m, 2H), 7.40-7.51 (m, 1 H), 7.13- [M + H]+/ 7.18 (m, 1 H), 6.99 (dd, J =0.8, 8 Hz, 2 H), 6.84 Method C (td, J = 1.6, 8.4 Hz, 1 H), 6.69-6.77 (m,2 H), 4.37 (t, J = 4.4 Hz, 2 H), 4.04-4.08 (m, 2 H), 3.74-3.83 (m, 1 H),3.70 (t, J = 4.4 Hz, 2 H), 3.56 (t, J = 10 Hz, 2 H), 2.44-2.54 (m, 2 H),1.79 (d, J = 11.2 Hz, 2 H). 5.48 Rt = 2.51 ¹H NMR (400 MHz, DMSO) δ[ppm] at 90° C.: min, m/z = 10.42 (br s, 1 H), 8.79 (s, 1 H), 8.41-8.45(m, 1 H), 589.17 7.75 (t, J = 7.2 Hz, 1 H), 7.66 (t, J = 9.2 Hz, 1 H),[M + H]+/ 6.97 (d, J = 7.6 Hz, 1 H), 6.81 (t, J = 7.2 Hz, 2 H), Method C6.67-6.75 (m, 2 H), 4.36 (t, J = 4 Hz, 2 H), 3.88 (t, J = 4 Hz, 4 H),3.69 (br s, 2 H), 3.33 (br s, 4 H). 5.49 Rt = 2.35 ¹H NMR (400 MHz,DMSO) δ [ppm]: 10.72 (s, 1 min, m/z = H), 8.85 (s, 1 H), 8.41 (d, J =8.4 Hz, 1 H), 7.95 (d, 522.34 J = 6.4 Hz, 1 H), 7.46 (s, 1 H), 7.02 (d,J = 6.8 Hz, [M + H]+/ 1 H), 6.82-6.86 (m, 1 H). 6.70-6.78 (m, 2 H), 4.38Method C (t, J = 4.4 Hz, 2 H), 3.89 (br s, 4 H), 3.69 (br s, 2 H), 3.32(br s, 4 H). 5.50 Rt = 2.99 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.68 (s, 1min, m/z = H), 8.73 (s, 1 H), 8.27 (d, J = 7.6 Hz, 1 H), 7.72 (t, 513.26J = 7.2 Hz, 1 H), 7.55 (d, J = 6 Hz, 1 H), 6.99 (d, [M + H]+/ J = 9.6Hz, 3 H), 6.71 (quint, J = 1.2, 8.4 Hz, 1 H), Method C 6.69-6.77 (m, 2H), 4.37 (t, J = 4 Hz, 2 H), 3.89 (br s, 4 H), 3.67 (br s, 2 H), 3.32(br s , 4 H). 5.51 Rt = 2.15 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.75 (s, 1min, m/z = H), 8.94 (s, 1 H), 8.46 (d, J = 7.6 Hz, 1 H), 8.42 (s, 597.281 H), 8.36 (d, J = 7.2 Hz, 1 H), 7.84 (t, J = 8 Hz, 1 [M + H]+/ H), 7.03(d, J = 8 Hz, 1 H), 6.86 (quint, J = 1.6, 8.4 Method C Hz, 1 H),671-6.79 (m, 2 H), 4.39 (t, J = 4 Hz, 2 H), 3.90 (br s, 4 H), 3.71 (brs, 2 H), 3.32 (br s, 4 H), 3.24 (quad, J = 7.2 Hz, 2 H), 1.41 (t, J =7.2 Hz, 3 H). 5.52 Rt = 1.75 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.73 (s, 1min, m/z = H), 8.79 (s, 1 H), 8.39 (d, J = 8 Hz, 1 H), 7.97 (d, 643.28 J= 6.4 Hz, 1 H), 7.77 (t, J = 8 Hz, 1 H), 7.60 (s, 1 [M + H]+/ H), 7.52(d, J = 6.8 Hz, 2 H), 7.35-7.42 (quad, J = Method C 6.8 Hz, 3 H), 7.01(d, J = 7.6 Hz, 1 H), 6.84 (t, J = 7.2 Hz, 1 H), 671-6.79 (m, 2 H), 5.50(s, 2 H), 4.39 (t, J = 4 Hz, 2 H), 3.90 (br s, 4 H), 3.70 (br s, 2 H),3.31 (br s , 4 H). 5.53 Rt = 1.85 ¹H NMR (400 MHz, DMSO + D₂O exchangeat min, m/z = 90° C.) δ [ppm]: 9.24 (s, 1 H), 8018 (t, J = 7.2 Hz,480.20 1 H), 7.86 (d, J = 6.8 Hz, 1 H), 7.78 (t, J = 7.6 Hz, [M + H]+/ 1H), 7.42-7.44 (m, 1 H), 7.14-7.16 (m, 1 H), 6.88 Method C (d, J = 7.2Hz, 1 H), 6.73-6.77 (m, 3 H), 4.37 (br s, 2 H), 3.66 (br s, 2 H). 5.54Rt = 2.52 ¹H NMR (400 MHz, DMSO) δ [ppm]: 9.92 (s, 1 H), min, m/z = 8.82(s, 1 H), 8.40-8.44 (m, 1 H), 7.89 (t, J = 7.2 573.27 Hz, 1 H), 7.73 (t,J = 9.2 Hz, 1 H), 7.15 (d, J = 7.2 [M + H]+/ Hz, 1 H), 7.09 (t, J = 7.6Hz, 1 H), 6.78-8.83 (m, 2 Method C H), 3.89 (t, J = 3.6 Hz, 4 H),3.65-3.72(m, 2H), 3.32 (br s, 4H), 3.02 (t, J = 7.6 Hz, 2 H). 5.55 Rt =2.31 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.6 (s, 1 H), min, m/z = 8.96 (s,1 H), 8.72 (d, J = 8.4 Hz, 1 H), 7.90 (d, J = 494.31 6.8 Hz, 1 H), 7.81(t, J = 8 Hz, 1 H), 7.63-7.66 (m, [M + H]+/ 1H), 7.26-7.29 (m 1 H), 6.84(t, J = 7.6 Hz, 1 H), Method C 6.71-6.77 (m, 2 H), 5.18 (br s, 1 H),4.37 (t, J = 4 Hz, 2 H), 3.68 (br s, 2 H), 3.23 (s, 3 H), 1.70 (d, J =6.8 Hz, 3 H). 5.56 Rt = 2.42 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.60 (s, 1min, m/z = H), 8.75 (s, 1 H), 8.38-8.42 (m, 1 H), 7.86-7.89 (t, 545.30 J= 7.2 Hz, 1 H), 7.68 (t, J = 8.8 Hz, 1 H), 6.99 (dd, [M + H]+/ J = 1.2,8 Hz, 1 H), 6.81 (td, J = 1.6, 8.8 Hz, 1 H), Method C 6.72-6.77 (m, 2H), 4.37 (t, J = 4.4 Hz, 2 H), 3.66 (d, J = 3.6 Hz, 2 H), 3.10 (s, 6 H).5.57 Rt = 2.18 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.70 (s, 1 min, m/z =H), 8.82 (s, 1 H), 8.39 (d, J = 7.6 Hz, 1 H), 7.95- 539.72 8.05 (m, 2H), 7.80 (t, J = 8.4 Hz, 2 H), 7.01 (dd, [M + H]+/ J = 1.2, 8 Hz, 1 H),6.83 (td, J = 1.2, 8 Hz, 1 H), Method C 6.74-6.78 (m, 2 H), 4.38 (t, J =4 Hz, 2 H), 3.90 (br s, 2 H), 3.69 (br s, 4 H), 3.32 (s, 4 H). 5.58 Rt =2.28 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.52 (s, 1 min, m/z = H), 8.89 (s,1 H), 8.78-8.82 (m, 1 H), 7.85-7.93 (m, 544.25 2 H), 6.98 (d, J = 8 Hz,1 H), 6.82 (t, J = 6.8 Hz, 1 [M + H]+/ H), 6.70-6.77 (m, 2 H), 4.39 (t,J = 4 Hz, 2 H), 3.71 Method D (br s, 2 H), 1.23-1.34 (m, 3 H), 0.71-0.78(m, 2 H). 5.59 Rt = 2.51 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.72 (s, 1min, m/z = H), 8.85 (s, 1 H), 8.39-8.43 (m, 1 H), 8.21 (s, 3 H), 621.147.73 (t, J = 9.6 Hz, 1 H), 7.00 (d, J = 6.8 Hz, 1 H), [M + H]+/ 6.83(td, J = 1.6, 8 Hz, 1 H), 6.71-6.78 (m, 2 H), Method D 4.37 (t, J = 4Hz, 2 H), 3.89 (t, J = 4 Hz, 2 H), 3.69 (br s, 2 H), 3.29 (t, J = 4 Hz,4 H). 5.60 Rt = 2.25 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.71 (s, 1 min,m/z = H), 8.85 (s, 1 H), 8.40-8.44 (m, 1 H), 7.84-7.89 (m, 555.31 1 H),7.73 (t, J = 9.2 Hz, 1 H), 7.47 (br s, 1 H), 7.01 [M + H]+/ (d, J = 7.6Hz, 1 H), 6.83 (t, J = 7.2 Hz, 1 H), 6.69- Method C 6.77 (m, 2 H), 4.38(t, J = 4.4 Hz, 2 H), 3.89 (br s, 2 H), 3.69 (br s, 2 H), 3.29 (br s, 4H). 5.61 Rt = 2.40 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.71 (s, 1 min, m/z= H), 8.85 (s, 1 H), 8.37-8.41 (m, 1 H), 7.97 (s, 1 H), 587.39 7.91 (s,1 H), 7.82 (s, 1 H), 7.71 (t, J = 9.2 Hz, 1 [M + H]+/ H), 7.01 (d, J = 8Hz, 1 H), 6.83 (t, J = 7.2 Hz, 1 Method C H), 6.71-6.77 (m, 2 H), 4.37(br s, 2 H), 3.89 (br s, 4 H), 3.69 (br s, 2 H), 3.29 (br s, 4 H). 5.62Rt = 2.43 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.29 (s, 1 min, m/z = H),8.84 (s, 1 H), 8.33-8.37 (m, 1 H), 7.91 (t, J = 7.6 563.22 Hz, 1 H),7.79 (t, J = 9.2 Hz, 1 H), 7.11 (d, J = 7.6 [M + H]+/ Hz, 1 H), 6.83 (t,J = 6.8 Hz, 1 H), 6.67-6.75 (m, 2 Method C H), 4.36 (t, J = 3.6 Hz, 2H), 3.62 (br s, 2 H), 3.58 (s, 3 H), 3.32 (br s, 2 H). 5.63 Rt = 2.48 ¹HNMR (400 MHz, DMSO) δ [ppm] 90° C.: min, m/z = 10.43(s, 1 H), 8.78 (s, 1H), 8.32 (d, J = 7.6 Hz, 1 535.30 H), 7.70-7.84 (m, 6 H), 6.98 (d, J =7.6 Hz, 1 H), [M + H]+/ 6.83 (t, J = 6.8 Hz, 1 H), 6.68-6.76 (m, 2 H),4.37 Method C (t, J = 4.4 Hz, 2 H), 3.89 (t, J = 4.4 Hz, 4 H), 3.71 (t,J = 4.4 Hz, 2 H), 3.33 (t, J = 4.4 Hz, 4 H). 5.64 Rt = 2.47 ¹H NMR (400MHz, DMSO) δ [ppm]: 10.72 (s, 1 min, m/z = H), 8.89 (s, 1 H), 8.36 (d, J= 8.4 Hz, 1 H), 7.97 (s, 603.24 3 H), 7.76 (t, J = 8 Hz, 1 H), 7.03 (d,J = 8 Hz, 1 [M + H]+/ H), 6.82 (t, J = 7.2 Hz, 1 H), 6.72-6.78 (m, 2 H),Method C 4.39 (br s, 2 H), 3.89 (br s, 4 H), 3.71 (br s, 2 H), 3.31 (s,4 H). 5.65 Rt = 2.25 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.71 (s, 1 min,H), 8.86 (s, 1 H), 847-8.51 (m, 1 H), 8.20 (quad, m/z = J = 7.6 Hz, 1H), 7.78 (t, J = 8.8 Hz, 1 H), 7.01 (d, 573.25 J = 8 Hz, 1 H), 6.82 (t,J = 7.2 Hz, 1 H), 6.69-6.77 [M + H]+/ (m, 2 H), 4.37 (t, J = 4.4 Hz, 2H), 3.89 (br s, 4 H), Method C 3.68 (br s, 2 H), 3.31 (s, 4 H). 5.66 Rt= 2.11 ¹H NMR (400 MHz, DMSO) δ [ppm]: 10.72 (s, 1 min, H), 8.88 (s, 1H), 8.33 (d, J = 8.4 Hz, 1 H), 8.07 (d, m/z = J = 9.6 Hz, 1 H), 7.93 (d,J = 7.2 Hz, 1 H), 7.75 (t, 526.15 J = 8 Hz, 1 H), 7.03 (d, J = 8 Hz, 1H), 6.85 (t, J = [M + H]+/ 7.2 Hz, 1 H), 6.70-6.78 (m, 2 H), 4.39 (br s,2 H), Method C 3.89 (br s, 4 H), 3.70 (br s, 2 H), 328 (br s, 4 H). 5.67Rt = 2.00 min, m/z = 528.31 [M + H]+/ Method C 5.68 Rt = 2.26 min, m/z =532.30 [M + H]+/ Method C

The compounds of formula (I) of the present invention are useful for thetreatment and/or control, in particular helminths, in which theendoparasitic nematodes and trematodes may be the cause of seriousdiseases of mammals and poultry. Typical nematodes of this indicationare: Filariidae, Setariidae, Haemonchus, Trichostrongylus, Ostertagia,Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia,Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis,Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris andParascaris. The trematodes include, in particular, the family ofFasciolideae, especially Fasciola hepatica.

Certain parasites of the species Nematodirus, Cooperia andOesophagostonum infest the intestinal tract of the host animal, whileothers of the species Haemonchus and Ostertagia are parasitic in thestomach and those of the species Dictyocaulus are parasitic in the lungtissue. Parasites of the families and may be found in the internal celltissue and in the organs, e.g. the heart, the blood vessels, the lymphvessels and the subcutaneous tissue. A particularly notable parasite isthe heartworm of the dog, Dirofilaria iminitis.

The parasites which may be treated and/or controlled by the compounds offormula (I) also include those from the class of Cestoda (tapeworms),e.g. the families Mesocestoidae, especially of the genus Mesocestoides,in particular M. lineatus; Dipylidiidae, especially Dipylidium caninum,Joyeuxiella spp., in particular Joyeuxiella pasquali, and Diplopylidiumspp., and Taeniidae, especially Taenia pisformis, Taenia cervi, Taeniaovis, Taeneia hydatigena, Taenia multiceps, Taenia taeniaeformis, Taeniaserialis, and Echinococcus spp., most particularly Taneia hydatigena,Taenia ovis, Taenia multiceps, Taenia serialis; Echinococcus granulosusand Echinococcus multilocularis.

Furthermore, the compounds of formula (I) are suitable for the treatmentand/or control of human pathogenic parasites. Of these, typicalrepresentatives that appear in the digestive tract are those of thegenus Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella,Capillaria, Trichuris and Enterobius. The compounds of the presentinvention are also against parasites of the genus Wuchereria, Brugia,Onchocerca and Loa from the family of Dracunculus and parasites of thegenus Strongyloides and Trichinella, which infect the gastrointestinaltract in particular.

A particular parasite to be treated and/or and controlled by thecompounds of the invention is the heartworm (Dirofilaria immitis).Particular subjects for such treatment are dogs and cats.

The compounds of the invention can be administered alone or in the formof a composition. In practice, the compounds of the invention areusually administered in the form of compositions, that is, in admixturewith at least one acceptable excipient. The proportion and nature of anyacceptable excipient(s) are determined by the properties of the selectedcompound of the invention, the chosen route of administration, andstandard practice as in the veterinary and pharmaceutical fields.

In one embodiment, the present invention provides compositionscomprising: a compound of invention and at least one acceptableexcipient.

In effecting such treatment and/or control, a compound of the inventioncan be administered in any form and route which makes the compoundbioavailable. The compounds of the invention can be administered by avariety of routes, including orally, in particularly by tablets andcapsules. The compounds of the invention can be administered parenteralroutes, more particularly by inhalation, subcutaneously,intramuscularly, intravenously, intraarterially, transdermally,intranasally, rectally, vaginally, occularly, topically, sublingually,and buccally, intraperitoneally, intraadiposally, intrathecally and vialocal delivery for example by catheter or stent. One skilled in the artcan readily select the proper form and route of administration dependingupon the particular characteristics of the compound selected, thedisorder or condition to be treated, the stage of the disorder orcondition, and other relevant circumstances. The pharmaceuticalcompositions of the invention may be administered to the subject, forexample, in the form of tablets, capsules, cachets, papers, lozenges,wafers, elixirs, ointments, transdermal patches, aerosols, inhalants,suppositories, drenches, solutions, and suspensions.

The term “acceptable excipient” refers to refers to those typically usedin preparing veterinary and pharmaceutical compositions and should bepure and non-toxic in the amounts used. They generally are a solid,semi-solid, or liquid material which in the aggregate can serve as avehicle or medium for the active ingredient. Some examples of acceptableexcipients are found in Remington's Pharmaceutical Sciences and theHandbook of Pharmaceutical Excipients and include diluents, vehicles,carriers, ointment bases, binders, disintegrates, lubricants, glidants,sweetening agents, flavoring agents, gel bases, sustained releasematrices, stabilizing agents, preservatives, solvents, suspendingagents, buffers, emulsifiers, dyes, propellants, coating agents, andothers.

In one embodiment, the composition is adapted for oral administration,such as a tablet or a capsule or a liquid formulation, for example, asolution or suspension, adapted for oral administration. In oneembodiment, the composition is adapted for oral administration, such aschewable formulation, adapted for oral administration. In still anotherembodiment, the composition is a liquid or semi-solid formulation, forexample, a solution or suspension or a paste, adapted for parenteraladministration.

Particular compositions for usage on subjects in the treatment and/orcontrol of nematodes/helminths comprise solutions; emulsions includingclassical emulsions, microemulsions and self-emulsifying compositions,that are waterless organic, preferably oily, compositions which formemulsions, together with body fluids, upon addition to the subject'sbody; suspensions (drenches); pour-on formulations; food additives;powders; tablets including effervescent tablets; boli; capsulesincluding micro-capsules; and chewable treats. Particularly compositionforms are tablets, capsules, food additives or chewable treats.

The compositions of the present invention are prepared in a manner wellknown in the veterinary and pharmaceutical art and include at least oneof the compounds of the invention as the active ingredient. The amountof a compound of the present invention may be varied depending upon itsparticular form and may conveniently be between 1% to about 50% of theweight of the unit dose form. The present pharmaceutical compositionsare preferably formulated in a unit dose form, each dose typicallycontaining from about 0.5 mg to about 100 mg of a compounds of theinvention. One or more unit dose form(s) may be taken to affect thetreatment dosage.

In one embodiment, the present invention also provides a method fortreating parasites, comprising: administering to a subject in needthereof an effective amount of a compound of formula (I) or a saltthereof, the method optionally further comprising an effective amount ofat least one additional active compound.

In one embodiment, the present invention also provides a method forcontrolling parasites, comprising: administering to a subject in needthereof an effective amount of a compound of formula (I) or a saltthereof, the method optionally further comprising an effective amount ofat least one additional active compound.

In one embodiment, the present invention also provides a method fortreating or controlling parasites, comprising: contacting a subject'senvironment with an effective amount of a compound of formula (I) or asalt thereof, the method optionally further comprising an effectiveamount of at least one additional active compound.

Thus, the invention provides for the use of the compounds of theinvention as a medicament, including for the manufacture of amedicament. In one embodiment, the invention provides the manufacture ofa medicament comprising a compound of formula (I) or a salt thereof fortreating parasites. In one embodiment, the invention provides themanufacture of a medicament comprising a compound of the invention or asalt thereof for controlling parasites.

The terms “treating”, “to treat”, “treated”, or “treatment”, includewithout limitation restraining, slowing, stopping, reducing,ameliorating, reversing the progression or severity of an existingsymptom, or preventing a disorder, condition, or disease. For example,an adult heartworm infection would be treated by administering acompound of the invention. A treatment may be applied or administeredtherapeutically.

The terms “control”, “controlling” or “controlled” refers to includewithout limitation decreasing, reducing, or ameliorating the risk of asymptom, disorder, condition, or disease, and protecting an animal froma symptom, disorder, condition, or disease. Controlling may refer totherapeutic, prophylactic, or preventative administration. It is wellunderstood that a larvae or immature heartworm infection may beasymptomatic and infection by mature parasites is symptomatic and/ordebilitating. Therefore, for example, a heartworm infection would becontrolled by acting on the larvae or immature parasite preventing theinfection from progressing to an infection by mature parasites.

Thus, the use of the compounds of the invention in the treatment and/orcontrol of parasites, in particular helminths, in which theendoparasitic nematodes and trematodes refers to the use of thecompounds of the invention to act on the various forms of the parasitesthroughout its life cycle, independent of whether a subject ismanifesting a symptom, including morbidity or mortality, andindependently of the phase(s) of the parasitic challenge.

As used herein, “administering to a subject” includes but is not limitedto cutaneous, subcutaneous, intramuscular, mucosal, submucosal,transdermal, oral or intranasal administration. Administration couldinclude injection or topical administration.

The terms “subject” and “patient” refers includes humans and non-humanmammalian animals, such as dogs, cats, mice, rats, guinea pigs, rabbits,ferrets, cows, horses, sheep, goats, and pigs. It is understood that amore particular subject is a human. Also, a more particular subject aremammalian pets or companion animals, such as dogs and cats and alsomice, guinea pigs, ferrets, and rabbits.

The term “effective amount” refers to an amount which gives the desiredbenefit to the subject and includes administration for both treatmentand control. The amount will vary from one individual subject to anotherand will depend upon a number of factors, including the overall physicalcondition of the subject and the severity of the underlying cause of thecondition to be treated, concomitant treatments, and the amount ofcompound of the invention used to maintain desired response at abeneficial level.

An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount, the dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of patient; its size, age, and general health; thespecific condition, disorder, infection, or disease involved; the degreeof or involvement or the severity of the condition, disorder, ordisease, the response of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances. An effective amount of the present invention, thetreatment dosage, is expected to range from 0.5 mg to 100 mg. Specificamounts can be determined by the skilled person. Although these dosagesare based on a subject having a mass of about 1 kg to about 20 kg, thediagnostician will be able to determine the appropriate dose for asubject whose mass falls outside of this weight range. An effectiveamount of the present invention, the treatment dosage, is expected torange from 0.1 mg/kg to 10 mg/kg of the subject. The dosing regimen isexpected to be daily, weekly, or monthly administration.

The compounds of the invention may be combined with one or more otheractive compounds or therapies for the treatment of one or moredisorders, diseases or conditions, including the treatment of parasites,for which it is indicated. The compounds of the invention may beadministered simultaneously, sequentially or separately in combinationwith one or more compounds or therapies for treating parasites and otherdisorders.

For example, when used to treat parasites, including heartworm, acompound of the invention may be combined with a macrocyclic lactonesuch as ivermectin, moxidectin, or milbemycin oxime, or withimidacloprid. Particular combinations for treating parasites include acompound of the invention and ivermectin. Another particular combinationfor treating parasites include a compound of the invention andmilbemycin oxime.

Thus, it is understood that the compositions and methods of the presentinvention optionally include comprising an effective amount of at leastone additional active compound.

The activity of compounds as parasiticides may be determined by avariety of methods, including in vitro and in vivo methods.

Example A Dog Heart Worm Microfilariae

D. immitis microfilariae are isolated by filtration from beagle blood ofan infected donor and allowed to incubate in appropriate media. Testcompounds are diluted in DMSO and added to a 96-well plate containingparasites. Plates are incubated for the desired time and motility isassessed using an LCD camera imaging system. Effect of serum is testedby addition of up to 20% fetal bovine serum in the assay. Percentmotility inhibition values are generated relative to the average of theDMSO-only wells.

In this test for example, the following compounds from the preparationexamples showed EC₅₀<0.1 μg/mL: 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,3.1, 3.2, 3.3, 3.4, 4.1, 5.1, 5.2, 5.3, 5.4, 5.6, 5.7, 5.8, 5.10, 5.11,5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23,5.23, 5.24, 6.1, and 7.1.

Example B1

Ruminant gastrointestinal (H. contortus Larval Development Assay (HcLDA)):

H.c. eggs isolated from lamb fecal matter are allowed to hatchovernight. Test compounds are diluted in DMSO and added to a 96-wellplate containing appropriate media. H.c. larvae are added to each welland plates are incubated for the desired time(s). Motility is assessedusing an LCD camera imaging system. Percent motility inhibition valuesare generated relative to the average of the DMSO-only wells.

In this test for example, the following compounds from the preparationexamples showed EC₅₀<1 μg/mL: 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.8, 3.1,3.2, 3.3, 3.4, 4.1, 5.1, 5.2, 5.3, 5.4, 5.6, 5.7, 5.8, 5.11, 5.12, 5.13,5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.23, 5.24,6.1, and 7.1.

Example B2 Other Nematodes In Vitro

Caenorhabditis elegans (Ce): C. elegans development assay (Ce DA)measures the effect of compounds on developing nematodes. Eggs of C.elegans are deposited in a 384 well plate together with food (E. coli)and the treatment formulated in DMSO. Plates are incubated at 25° C. for48 h to allow the development of nematodes up to the L4-stage. Theeffect of compounds is measured as motility reduction. Efficacy isexpressed in % motility reduction compared to negative controls.

In this test for example, the following compounds from the preparationexamples showed EC₉₀<1 μg/mL: 5.23, 5.35, 5.36, 5.41, 5.45, 5.47, 5.48,5.49, 5.54, 5.55, 5.56, 5.57, 5.58, 5.59, 5.60, 5.61, 5.62, 5.63.

Example C Gastro Intestinal Nematodes

Jirds (Meriones unguiculatus), are artificially infected by gavage withthird instar larvae each of T. colubriformis and H. contortus. Thentreated orally with the test compound formulated in eg DMSO/PEG 2/1, onDay 6 after infection at a dose in a range between 1×3 mg/kg up to 1×32mg/kg. Three days after treatment, gerbils are euthanized and dissectedto recover H. contortus from stomach and T. colubriformis from the smallintestine. Efficacy is expressed as a % reduction in worm numbers incomparison with a placebo treated group, using the Abbot's formula.

The compound of examples 3.3, 5.2, 5.3, 5.4, 5.19, 5.23 and 5.47were >80% effective against Hc and Tc. The compound of examples 3.1, 2.3and 5.6 were >80% effective against Hc.

Example D Filarial Nematodes

Av model: Gerbils, injected subcutaneously with infective A. viteaelarvae, were subsequently treated with the test article formulated in egDMSO/PEG 2/1, by oral gavage at a dose in a range between 1×3 mg/kg upto 5×32 mg/kg (one dose per day for 5 consecutive days). At necropsy 12weeks after infection, efficacy is expressed as a % reduction in wormnumbers in comparison with the placebo treated group, using the Abbot'sformula.

The compound of examples 2.6, 3.4, 5.4, 5.6, 5.7, 5.8, 5.19 and 5.20were >80% effective against Av.

Example E

L.s. Model

Mice (BALB/c) were experimentally infected with 3rd stage larvae of L.sigmodontis, either by subcutaneous injection or by exposure to infectedmites. Treatment was done with test article formulated in DMSO/PEG at aratio 2/1, by oral gavage or subcutaneous injection at a dose in a rangebetween 1×3 mg/kg (single dose) up to 5×32 mg/kg (one dose per day for 5consecutive days). At necropsy 35 to 37 days after infection, worms arecounted in the peritoneum and the pleural cavity. Efficacy is expressedas % reduction in worm numbers in comparison with the placebo treatedgroup, using the Abbot's formula. The compound of examples 3.3, 5.3,5.41, 5.47, 5.48 and 5.56 were >80% effective against L.s.

1. A compound of formula (I):

wherein n is 0 or 1; X₁ is selected from the group consisting of N andCR₁; X₂ is selected from the group consisting of N and CR₂; X₃ isselected from the group consisting of N and CR₃; X₄ is selected from thegroup consisting of N and CR₄; X₅ is selected from the group consistingof N and CR₅; X₆ is selected from the group consisting of N and CR₆; Gis selected from the group consisting of

M is selected from the group consisting of N—R₁₃, O, and S; Y₁ isselected from the group consisting of CR₈R₉, O, S, and NR₁₀; Y₂ isselected from the group consisting of CR₈R₉, O, S, and NR₁₀; wherein atleast one of the groups Y₁ or Y₂ is CR₈R₉; Z₁ is selected from the groupconsisting of N, O, S, and CR₁₁; Z₂ is selected from the groupconsisting of nil, N, and CR₁₁; Z₃ is selected from the group consistingof nil, N and CR₁₁; Z₄ is selected from the group consisting of N, O, S,and CR₁₁; wherein no more than 2 of Z₁, Z₂, Z₃, and Z₄ are N and whereinonly one of Z₁ and Z₄ is O or S, Z₂ is nil only when Z₁ is O or S, andZ₃ is nil only when Z₄ is O or S; R₁ is selected from the groupconsisting of hydrogen, halogen, hydroxyl, —SH, —SC₁-C₄ alkyl,—S(O)(C₁-C₄ alkyl), —S(O)₂(C₁-C₄ alkyl), cyano, C₁-C₄ alkyl, C₁-C₄halogenoalkyl, C₁-C₄-alkoxy, —B(OR₁₅)(OR₁₆) wherein R₁₅ is, each timetaken, selected from the group consisting of hydrogen, C₁-C₄ alkyl, andC₃-C₆ cycloalkyl, R₁₆ is, each time taken, selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or R₁₅ andR₁₆ together with the oxygen atoms to which they are attached form a 5-to 7-membered ring which is optionally substituted with 1 to 4 C₁-C₄alkyl; —NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂; R₂ is selected fromthe group consisting of hydrogen, halogen, hydroxyl, —SH, —SC₁-C₄ alkyl,—S(O)(C₁-C₄ alkyl), —S(O)₂(C₁-C₄ alkyl), cyano, C₁-C₄ alkyl, C₁-C₄halogenoalkyl, C₁-C₄-alkoxy, —B(OR₁₅)(PR₁₆) wherein R₁₅ is, each timetaken, selected from the group consisting of hydrogen, C₁-C₄ alkyl, andC₃-C₆ cycloalkyl, R₁₆ is, each time taken, selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or R₁₅ andR₁₆ together with the oxygen atoms to which they are attached form a 5-to 7-membered ring which is optionally substituted with 1 to 4 C₁-C₄alkyl; —NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂; R₃ is selected fromthe group consisting of hydrogen, halogen, hydroxyl, —SH, —SC₁-C₄ alkyl,—S(O)(C₁-C₄ alkyl), —S(O)₂(C₁-C₄ alkyl), cyano, C₁-C₄ alkyl, C₁-C₄halogenoalkyl, C₁-C₄-alkoxy, —B(OR₁₅)(PR₁₆) wherein R₁₅ is, each timetaken, selected from the group consisting of hydrogen, C₁-C₄ alkyl, andC₃-C₆ cycloalkyl, R₁₆ is, each time taken, selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or R₁₅ andR₁₆ together with the oxygen atoms to which they are attached form a 5-to 7-membered ring which is optionally substituted with 1 to 4 C₁-C₄alkyl; —NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂; R₄ is selected fromthe group consisting of halogen, cyano, —CHO, hydroxyl, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl,C₁-C₄-alkoxy substituted-C₁-C₄ alkyl, benzyl optionally substituted with1 to 5 halogen atoms, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —NH(C₃-C₆ cycloalkyl), —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl),—N(C₁-C₄ alkyl)(4- to 7-membered heterocycloalkyl), —NH(4- to 7-memberedheterocycloalkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkoxy), —C(O)NH(C₁-C₄ alkyl),—C(O)N(C₁-C₄ alkyl)₂, —C(O)N(C₁-C₄ alkyl)(4- to 7-memberedheterocycloalkyl), —NHSO₂(C₁-C₄ alkyl), —SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl,—SO₂C₁-C₄ alkyl, —B(OR₁₅)(OR₁₆) wherein R₁₅ is, each time taken,selected from the group consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆cycloalkyl, R₁₆ is, each time taken, selected from the group consistingof hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or R₁₅ and R₁₆ togetherwith the oxygen atoms to which they are attached form a 5- to 7-memberedring which is optionally substituted with 1 to 4 C₁-C₄ alkyl; 6- or 10membered aryl; a monocyclic heterocycle selected from the group of 4- to7-membered heterocycloalkyl, 5-membered heteroaryl having at least onenitrogen atom via which the 5-membered heteroaryl ring is connected tothe rest of the molecule, and 6-membered heteroaryl having at least onenitrogen atom; each of the aryl, heterocycloalkyl, and heteroaryl ringsin R₄ is optionally substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, cyano,nitro, hydroxy, oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl,C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆cycloalkyl), —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl),—SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,—S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl; wherein the C₃-C₆cycloalkyl and the heterocycloalkyl rings in R₄ are optionallysubstituted with a spiro group, wherein said spiro group is a 3- to6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1,2, or 3 heteroatoms independently selected from N, S or O, wherein saidspiro group is optionally substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, cyano,nitro, hydroxy, oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl,C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆cycloalkyl), —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl),—SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,—S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl; and wherein eachC₁-C₄ alkyl, C₃-C₆ cycloalkyl and C₁-C₄ alkoxy in R₄ may be optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halogen, hydroxy, NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, cyano, carboxy, carbamoyl, C₁-C₄ alkoxycarbonyl, —C(O)NH(C₁-C₄alkyl), —C(O)N(C₁-C₄ alkyl)₂, and C₁-C₄ alkoxy; R₅ is selected from thegroup consisting of hydrogen, halogen, hydroxyl, —SH, —SC₁-C₄ alkyl,—S(O)(C₁-C₄ alkyl), —S(O)₂(C₁-C₄ alkyl), cyano, C₁-C₄ alkyl, C₁-C₄halogenoalkyl, C₁-C₄-alkoxy, —B(OR₁₅)(OR₁₆) wherein R₁₅ is, each timetaken, selected from the group consisting of hydrogen, C₁-C₄ alkyl, andC₃-C₆ cycloalkyl, R₁₆ is, each time taken, selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or R₁₅ andR₁₆ together with the oxygen atoms to which they are attached form a 5-to 7-membered ring which is optionally substituted with 1 to 4 C₁-C₄alkyl; —NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂; R₆ is selected fromthe group consisting of hydrogen, halogen, hydroxyl, —SH, —SC₁-C₄ alkyl,—S(O)(C₁-C₄ alkyl), —S(O)₂(C₁-C₄ alkyl), cyano, C₁-C₄ alkyl, C₁-C₄halogenoalkyl, C₁-C₄-alkoxy, —B(OR₁₅)(OR₁₆) wherein R₁₅ is, each timetaken, selected from the group consisting of hydrogen, C₁-C₄ alkyl, andC₃-C₆ cycloalkyl, R₁₆ is, each time taken, selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl, or R₁₅ andR₁₆ together with the oxygen atoms to which they are attached form a 5-to 7-membered ring which is optionally substituted with 1 to 4 C₁-C₄alkyl; —NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂; R₇ is selected fromthe group consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyloptionally substituted with 1 to 5 halogen atoms, —C(H)O, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₄ halogenoalkyl, and C₁-C₄-alkoxy; R₈ is, each timeselected, independently selected from the group consisting of hydrogen,fluoro, and C₁-C₄ alkyl; R₉ is, each time selected, independentlyselected from the group consisting of hydrogen, fluoro, and C₁-C₄ alkyl;R₁₀ is selected from the group consisting of hydrogen and C₁-C₄ alkyl;R₁₁ is, each time selected, independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, cyano, C₁-C₄ alkyl, C₁-C₄halogenoalkyl, C₁-C₄-alkoxy, C₃-C₆ cycloalkyl, —NH₂, —NH(C₁-C₄ alkyl),and —N(C₁-C₄ alkyl)₂; Q is selected from the group consisting of (i) 6-or 10 membered aryl optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting ofhalogen, cyano, nitro, hydroxyl, C₁-C₄ alkyl, C₁-C₄ halogenoalkyl, C₁-C₄alkoxy, C₃-C₆ cycloalkyl, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—NH(C₃-C₆ cycloalkyl), —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄alkyl), —SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,—S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl, wherein the 6- or10 membered aryl is optionally fused with a 4- to 7-memberedheterocycloalkyl having 1 or 2 heteroatoms selected from the group O, S,and N and wherein the carbons of the heterocycloalkyl are optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup halogen, cyano, nitro, hydroxyl, oxo, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl),and —N(C₁-C₄ alkyl)₂ and any N in the heterocycloalkyl is, valencypermitting, substituted with a substituent selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl; (ii) 5- to10-membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from the group O, S, and N and wherein the carbons of the 5- to10-membered heteroaryl are optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting ofhalogen, cyano, nitro, hydroxyl, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄halogenoalkyl, C₁-C₄ alkoxy, benzyloxy, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,—S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl, and any N in theheteroaryl, valency permitting, is optionally substituted with asubstituent selected from the group consisting of hydrogen, C₁-C₄ alkyl,and C₃-C₆ cycloalkyl; (iii) 4- to 7-membered heterocycloalkyl having 1,2, or 3 heteroatoms independently selected from the group O, S, N,wherein the heterocycloalkyl is optionally benzo-fused, wherein thecarbons of the 4- to 7-membered heterocycloalkyl or optionallybenzo-fused 4- to 7-membered heterocycloalkyl are optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from the groupconsisting of halogen, cyano, nitro, hydroxyl, oxo, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl),and —N(C₁-C₄ alkyl)₂ and any N in the heterocycloalkyl is optionallysubstituted with a substituent selected from the group consisting ofhydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl; (iv) 6- or 10 memberedaryloxy optionally substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of halogen, cyano, nitro, hydroxyl,C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂,—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl), —N(C₁-C₄alkyl)(C₃-C₆-cycloalkyl), —NHSO₂ (C₁-C₄ alkyl), —SC₁-C₄ alkyl,—S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl, —S(O)C₁-C₄-halogenoalkyl and—SO₂C₁-C₄ halogenoalkyl; (v) 6- or 10 membered arylthio-oxy optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halogen, cyano, nitro, hydroxyl, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl), —N(C₁-C₄alkyl)(C₃-C₆-cycloalkyl), —NHSO₂ (C₁-C₄ alkyl), —SC₁-C₄ alkyl,—S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl, —S(O)C₁-C₄-halogenoalkyl and—SO₂C₁-C₄ halogenoalkyl; and (vi) 5- to 10-membered heteroaryloxyoptionally substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of halogen, cyano, nitro, hydroxyl,oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy,—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl),—N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl), —SC₁-C₄ alkyl,—S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl, —S(O)C₁-C₄-halogenoalkyl and—SO₂C₁-C₄ halogenoalkyl; R₁₃ is selected from the group consisting ofhydroxy, C₁-C₄ alkoxy, and —NH₂; and R₁₄ is, each time selected,independently selected from the group consisting of hydrogen, halogen,cyano, nitro, hydroxyl, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄halogenoalkyl, C₁-C₄ alkoxy, C₁-C₄ halogenalkoxy, —NH₂, —NH(C₁-C₄alkyl), and —N(C₁-C₄ alkyl)₂; or a salt thereof.
 2. The compoundaccording to claim 1 wherein X₁ is CR₁; X₂ is CR₂; X₃ is CR₃; X₄ is CR₄;X₅ is CR₅; and X₆ is N; or a salt thereof.
 3. The compound according toclaim 1 wherein X₁ is CR₁; X₂ is CR₂; X₃ is CR₃; X₄ is CR₄; X₅ is N; andX₆ is N; or a salt thereof.
 4. The compound according to claim 1 whereinX₁ is CR₁; X₂ is CR₂; X₃ is CR₃; X₄ is CR₄; X₅ is N; and X₆ is CR₆; or asalt thereof.
 5. The compound according to claim 1 wherein Q is a 6- or10 membered aryl optionally substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, cyano,nitro, hydroxy, C₁-C₄ alkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, C₃-C₆cycloalkyl, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NH(C₃-C₆cycloalkyl), —N(C₁-C₄ alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl),—SC₁-C₄ alkyl, —S(O)C₁-C₄ alkyl, —SO₂C₁-C₄ alkyl,—S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄ halogenoalkyl; or Q is a 5- to10-membered heteroaryl having 1 or 2 heteroatoms selected from the groupO, S, and N and wherein the carbons of the heteroaryl are optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halogen, cyano, nitro, —OH, C₁, C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy, —NH₂, —NH(C₁-C₄ alkyl),and —N(C₁-C₄alkyl)₂ and any N in the heteroaryl is optionallysubstituted with a substituent selected from the group consisting ofhydrogen, C₁-C₄ alkyl, and C₃-C₆ cycloalkyl; or a salt thereof. 6.-8.(canceled)
 9. The compound according to claim 1 wherein n is 1; Y₁ isCR₈R₉ and Y₂ is O; or a salt thereof.
 10. (canceled)
 11. The compoundaccording to claim 1 wherein R₄ is selected from the group consisting ofC₁-C₄ alkyl, C₃-C₆ cycloalkyl, —N(C₁-C₄ alkyl)₂, and 4- to 7-memberedheterocycloalkyl; or a salt thereof.
 12. The compound according to claim1 wherein G is

and M is O; or a salt thereof.
 13. The compound according to claim 1wherein G is

and M is O; or a salt thereof.
 14. The compound according to claim 1, ora salt thereof, having formula (Ia-5),

wherein R₁, R₄, and Q are as defined in claim
 1. 15. The compoundaccording to claim 14, or a salt thereof, wherein R₁ is hydrogen,halogen, or cyano.
 16. The compound according to claim 15, or a saltthereof, wherein R₁ is hydrogen or fluoro.
 17. The compound according toclaim 14, or a salt thereof, wherein R₄ is 4-morpholino ordimethylamino.
 18. The compound according to claim 14, or a saltthereof, wherein Q is a 6-membered aryl optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from the groupconsisting of halogen, cyano, nitro, hydroxyl, C₁-C₄ alkyl, C₁-C₄halogenoalkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —NH(C₃-C₆ cycloalkyl), —N(C₁-C₄alkyl)(C₃-C₆-cycloalkyl), —NHSO₂(C₁-C₄ alkyl), —SC₁-C₄ alkyl, —S(O)C₁-C₄alkyl, —SO₂C₁-C₄ alkyl, —S(O)C₁-C₄-halogenoalkyl and —SO₂C₁-C₄halogenoalkyl, wherein the 6- or 10 membered aryl is optionally fusedwith a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatomsselected from the group O, S, and N and wherein the carbons of theheterocycloalkyl are optionally substituted with 1, 2 or 3 substituentsindependently selected from the group halogen, cyano, nitro, hydroxyl,oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ halogenoalkyl, C₁-C₄ alkoxy,—NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂ and any N in theheterocycloalkyl is, valency permitting, substituted with a substituentselected from the group consisting of hydrogen, C₁-C₄ alkyl, and C₃-C₆cycloalkyl.
 19. The compound according to claim 14, or a salt thereof,wherein Q is selected from:


20. A compound of claim 1 selected from the group consisting of:N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl]-2,3-dihydro-1,4-benzoxazine-4-carboxamide;8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide;8-(3,5-dichlorophenyl)-N-(3,4-dihydro-2H-quinolin-1-yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide;8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7-naphthyridine-3-carboxamide;8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;5-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-1-(dimethylamino)naphthalene-2-carboxamide;8-(3,5-dichlorophenyl)-N-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-4-(dimethylamino)quinoline-3-carboxamide;or a salt of any of the foregoing compounds.
 21. A compound of claim 1selected from the group consisting of:N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-[methoxy(methyl)amino]-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide;8-[3-chloro-5-(trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7-naphthyridine-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3-dichlorophenyl)-1,7-naphthyridine-3-carboxamide;8-(3,5-dichloro-4-fluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7-naphthyridine-3-carboxamide;8-(5-chloro-3-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7-naphthyridine-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-thiomorpholino-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(3,4,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide;8-(2,3-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide;8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,5-naphthyridine-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,5-trifluorophenyl)-1,5-naphthyridine-3-carboxamide;8-(2,3-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;8-(5-chloro-3-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide;8-(3,5-difluorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-pyrimidin-5-yl-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-thiomorpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;8-[2-chloro-6-(trifluoromethyl)-4-pyridyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(2,6-dichloro-4-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(3,5-dichloro-2-fluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(5-chloro-2-fluoro-3-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(1,1-dioxo-1,4-thiazinan-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,4,5-trifluorophenyl)quinoline-3-carboxamide;8-(6-chloropyrazin-2-yl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(4,5-dichloro-3-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(5-chloro-2,3-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,4,5-tetrafluorophenyl)quinoline-3-carboxamide;8-(4-chloro-5-fluoro-3-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-[4-chloro-6-(trifluoromethyl)-2-pyridyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(3,5-dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;N-indolin-1-yl-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;8-(4,6-dichloro-2-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(6-fluoropyrazin-2-yl)-4-morpholino-quinoline-3-carboxamide;8-[2-chloro-6-(trifluoromethyl)pyrimidin-4-yl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(6-chloro-5-fluoro-2-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(6-chloro-3-fluoro-2-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(6-ethoxypyrazin-2-yl)-4-morpholino-quinoline-3-carboxamide;4-(azetidin-1-yl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-pyrrolidin-1-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-[2-methoxyethyl(methyl)amino]-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;4-[bis(2-methoxyethyl)amino]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;7-cyano-8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;4-cyclopropyl-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(3-fluoroazetidin-1-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(3-hydroxyazetidin-1-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-oxazolidin-3-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-8-(3,4,5-trifluorophenyl)quinoline-3-carboxamide;4-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxamide;and8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,6-naphthyridine-3-carboxamide;or a salt of any of the foregoing compounds.
 22. A compound of claim 1selected from the group consisting of:N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-isoxazolidin-2-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]quinoline-3-carboxamide;8-(2,6-dichloropyrimidin-4-yl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-tetrahydropyran-4-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;4-[acetyl(methyl)amino]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;8-(3,5-dichloro-2-fluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide;8-(3,5-dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,6-trifluoro-4-pyridyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(4-fluoro-2,6-dimethyl-phenyl)-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-[4-ethylsulfanyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-morpholino-quinoline-3-carboxamide;8-[4-benzyloxy-6-(trifluoromethyl)pyrimidin-2-yl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;[3-(2,3-dihydro-1,4-benzoxazin-4-ylcarbamoyl)-8-(2,3,5-trifluorophenyl)-4-quinolyl]boronicacid;8-(3,5-dichloro-2,4-difluoro-phenyl)-7-fluoro-N-indolin-1-yl-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(1-methoxyethyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;8-(3,5-dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-7-fluoro-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,5,6-tetrafluorophenyl)quinoline-3-carboxamide;4-cyclopropyl-8-(3,5-dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-quinoline-3-carboxamide;8-[3,5-bis(trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide;8-(5-chloro-2,3-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide;8-[3-chloro-5-(trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide;8-(3,5-dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-[methoxy(methyl)amino]quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide;8-[3,5-dichloro-4-(trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(3-chloro-2,5,6-trifluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide;8-(3-chloro-5-cyano-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;8-(3-cyano-2,5-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(2,2,2-trifluoro-1-methyl-ethyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;andN-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide;or a salt of any of the foregoing compounds. 23.-27. (canceled)
 28. Amethod of treating a parasitic infection, comprising administering to apatient in need thereof an effective amount of a compound according toclaim 1, or a salt thereof.
 29. A method of treating heartworminfection, comprising administering to a patient in need thereof aneffective amount of a compound according to claim 1, or a salt thereof.